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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
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Chapter 12. Anxiety Disorders
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

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).

even when these concomitant conditions are resolved.g." The differential diagnosis can sometimes become complicated when. They feel dizzy. social anxiety disorder. Patients experiencing their first panic attack generally fear they are having a heart attack or losing their mind.. electrocardiography.. where routine laboratory tests. and physical examination are performed. or separation anxiety disorder (e. a drug of abuse. on exposure to a specific phobic situation).g. The panic attacks are not better accounted for by another mental disorder. However. Panic disorder patients are usually young adults. lysergic acid diethylamide (LSD). C.g. cocaine. Panic attacks are well known to occur not only in panic disorder but in other anxiety disorders as well (e. on exposure to dirt in someone with an obsession about contamination). 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. posttraumatic stress disorder (e. historically. the loss of a close interpersonal relationship.g... the attacks often continue unabated. obsessive-compulsive disorder (e.g.g. 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. Patients developing either hypo. having a heart attack. However. The panic attacks are not due to the direct physiological effects of a substance (e. All that is found is an occasional case of sinus tachycardia.g. 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).g.. 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.Diagnostic criteria for 300. perhaps a few days or even weeks later they will again have the sudden onset of . starting college or accepting a job out of town). Clinical Description Onset In the typical onset of a case of panic disorder. and faint and are convinced they are about to die.g. Finally. Although the first attack generally strikes during some routine activity. one or several unexpected panic attacks initially occur in a specific situation. In these other disorders. especially marijuana.. specific phobia (e. light-headed. and amphetamines. 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. consistent with a diagnosis of panic disorder. and the patients are reassured and sent home. many patients have reported experiencing their first attacks while taking drugs of abuse. panic attacks are situationally bound or cued—that is. Attacks also begin in the immediate postpartum period. Not uncommonly. Such patients often rush to the nearest emergency department. and PTSD). individuals are engaged in some ordinary aspect of life when suddenly their heart begins to pound." "situationally bound (cued). in response to being away from home or close relatives). several events are often associated with the early presentation of panic disorder.. they occur exclusively within the context of the feared situation. in response to stimuli associated with a severe stressor).. sedatives. losing control.21 panic disorder with agoraphobia A. most likely in the third decade. Therefore clinical judgment regarding the preponderant clinical pattern is called for in making the differential diagnosis in such cases. 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. and specific phobia and specifies that panic attacks can occur as a feature of all three of these disorders. although onset may be as late as the sixth decade. hyperthyroidism). These patients may indeed feel reassured." or "situationally predisposed... a medication) or a general medical condition (e. or a separation from family (e. "going crazy") (c) a significant change in behavior related to the attacks B. such as social phobia (e. and at this point the diagnosis of panic disorder would be premature. D. specific phobia. social phobia.g. and they cannot catch their breath. The presence of agoraphobia.or hyperthyroidism may get the first flurry of attacks at this time. occurring on exposure to feared social situations).

g. and a sense of impending doom. and derealization characteristic of panic attacks. the patient usually develops a constant anticipatory anxiety characterized by continued apprehension about the possible occasion and consequences of the next attack. fearful of leaving home without a companion or even of staying home alone. planes). 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). hot and cold flashes. If the attacks continue. Many patients will . are also experienced: dyspnea. apprehension. At this point.severe anxiety with all of the associated physical symptoms. agitated depression. It is warranted to draw some further attention to what appears to be the cardinal symptom of panic. Typical agoraphobic fears are of using public transportation (e. terror. mostly physical. A number of lines of research evidence indicate that hyperventilation may be the central feature in the pathophysiology of panic attacks and panic disorder. subways. they may be told the problem is psychological. buses. chest pain or discomfort. and 3) fear of being away from home in situations where one can feel trapped. It is clear that most of the physical sensations of a panic attack represent massive overstimulation of the autonomic nervous system. feelings of unreality (derealization and/or depersonalization). 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. At times. choking or smothering sensations. the patient with so-called long panic attacks often has some other form of pathological anxiety. Several of a group of associated symptoms. or be referred for extensive medical workup. they seek emergency medical treatment. 2) fear of being alone. palpitations. being in crowds. However. or traveling a distance from home. presumably by dampening the ventilatory overreaction that may constitute the hallmark of panic. the diagnosis of panic disorder is only made when the attacks occur with some regularity and frequency. embarrassed. when he or she will experience the sudden onset of overwhelming fear. Symptoms Typically. leading to decreased cerebral blood flow and to the dizziness. or attending a concert. trembling and shaking. driving a car. attacks occur. Some patients continue to feel agitated and fatigued for several hours after the main portion of the attack has subsided. 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). subside. or losing control of oneself. eating in a restaurant. Indeed. In severe cases. The patient comes to dread experiencing an attack and starts worrying about doing so in the intervals between attacks. Attacks usually last from 5 to 20 minutes and rarely as long as an hour. This hyperventilation then induces hypocapnia and alkalosis. during a panic attack. such as severe generalized anxiety. the fear is one of developing distressing symptoms in such situations where escape is difficult or help is unavailable. dizziness or unsteady feelings. a patient will be engaged in a routine activity. paresthesias. waiting in line. or department stores. faintness. and a fear of dying. signs and symptoms of hyperventilation seem to disappear once a patient with panic disorder has been successfully treated with antipanic medication. theaters. Patients who claim they have attacks that last a whole day may fall into one of four categories.. Also. Most patients develop some degree of anticipatory anxiety consequent to the experience of repetitive panic attacks. According to DSM-IV-TR. Most cases of agoraphobia begin with a series of spontaneous panic attacks. trains. sweating. supermarkets. Again. 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. Such patients may be mistaken for GAD patients. restaurants. behavioral breathing retraining treatments aimed at teaching the patient not to hyperventilate are successful in decreasing the frequency of panic attacks. or helpless. elevators. leading to the DSM-IV-TR diagnosis of panic disorder with agoraphobia. or obsessional tension states. patients with occasional unexpected panic attacks may be genetically similar to patients with panic disorder. going crazy. and occur again in a wave-like manner. Agoraphobia Agoraphobia frequently develops in response to panic attacks. Alternatively. perhaps reading a book. Although many people experience an occasional unexpected attack of panic. confusion. in some cases. be given a prescription for a benzodiazepine tranquilizer. patients may be completely housebound. 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. Finally. Agoraphobic symptoms represent a tertiary phase in the illness. Some patients do not progress in their illness beyond the point of continuing to have unexpected panic attacks.

In other cases. In addition to panic attacks and chronic anxiety. FIGURE 12–2. The 1-month.5%. patient develops acute help-seeking behavior (X). start driving to work. For example. 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. and their attacks tended to continue longer into older age (Regier et al. such as crowded rooms. attacks may occur rarely or exclusively when the patient ventures into the feared situation. family member. 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. 1988). and 1. On the other hand. or close friend. They then avoid these situations in an attempt to prevent further panic attacks (Figure 12–2). bridges. and studies are further confounded because the presence of panic disorder may have secondary effects on personality. after the initial phase of the illness. multiple somatic complaints. front-row seats. (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. agoraphobic patients frequently exhibit symptoms of demoralization or secondary depression.7%. . Noyes et al. One interesting aspect of agoraphobia is the effect of a trusted companion on phobic behavior. then apprehension culminating in chronic anxiety (shaded areas). 6-month. and finally agoraphobic behavior (black blocks). Agoraphobic persons frequently fear situations in which they feel they cannot leave abruptly if an attack occurs. Some individuals continue to have spontaneous panic attacks throughout the course of the illness.8%. and lifetime prevalence rates for panic disorder at all five study sites combined were 0. respectively. Women had a 1-month prevalence rate of 0.3% rate found among men.causally relate their panic attacks to the particular situation in which the attacks have occurred. and airplanes. It is unclear whether vulnerability to panic attacks is actually decreased in this situation or whether the patient feels less helpless and isolated. which was significantly higher than the 0. Development of agoraphobia. women also tended to have a greater rise in panic disorder in the age range of 25 to 44 years. he interprets this as a sign that the attacks have spread to driving situations rather than as an indication that they were not. and alcohol or sedative drug abuse. After onset of unexpected panic attacks (solid bars).6%. 1988). 0. a man who has had several attacks while taking the train to work may attribute the attacks to the train and. in order to avoid the train. Many patients who are unable to leave the house alone can travel long distances and partake in most activities if accompanied by a spouse. If he still experiences panic attacks in the morning while driving to work rather than on the train. caused by the train. in the first place. Character Traits It has not been clearly established whether particular character types are correlated with panic disorder. tunnels.

if so. respectively (Grant et al. African American. however. and again the presence of agoraphobia was associated with greater symptom severity. agoraphobia without panic disorder was quite rare. respectively). Examination of various autonomic parameters seems to dispel the notion of simple autonomic dysregulation in panic (M. widowed/separated/divorced. in doses sufficient to achieve full peripheral -adrenergic blockade. such as propranolol. The National Comorbidity Survey Replication study reported highly similar findings. the overrepresentation of panic disorder with agoraphobia in treatment settings probably reflects greater treatment seeking and more severe disorder.7% for panic disorder without agoraphobia and 1. which included about 43. and for many years the possibility that panic attacks were manifestations of massive discharge from the -adrenergic nervous system was considered. only modest antianxiety effects can actually be demonstrated.17% lifetime prevalence. more severe symptoms. Stein and Asmundson 1994). was not able to block a sodium lactate–induced panic attack in patients with panic disorder (Gorman et al. in contrast to other agents that produce prominent physiological changes but fail to induce panic.000 participants. raising questions about its standing as a distinct Axis I disorder. and impairment.6% and 4. Being female. respectively. imaging. greater disability. B. Etiology Biological Theories There are a number of biological theories of panic disorder that figure prominently in the psychiatric literature. comorbidity. 1985a). with a lifetime prevalence of 3. and greater Axis I and II comorbidity compared with subjects without agoraphobia and were more likely to seek treatment early on. No study has ever shown that -adrenergic blockers are specifically effective in blocking spontaneous panic attacks.1%. revealed a 1-year and lifetime prevalence of panic disorder of 2. TABLE 12–4. even if these involve multiple neurochemicals and circuits. 2006). The -adrenergic hypothesis of panic has received -adrenergic blockers used in some support from studies claiming that -adrenergic–blocking drugs. The locus coeruleus has also been implicated in the pathogenesis of panic attacks. Native American.6% and 1. Indeed. whereas being Asian. or Hispanic decreased risk. It is not clear whether administration of catecholamines can actually provoke anxiety reactions and. 1998). On the other hand.1% with agoraphobia (Kessler et al. Certain agents have a powerful and specific capacity to induce panic. exceeding those of panic disorder with agoraphobia (0. Subjects with agoraphobia had an earlier age at onset. When the properly designed and controlled studies of specific well-diagnosed anxiety disorders are reviewed. symptoms of anxiety in human subjects. middle-aged. Elevated plasma levels of epinephrine are not. have an ameliorative effect on panic attacks and anxiety.1%. The theories are summarized in Table 12–4. neurochemical. but not necessarily the emotional. These findings argue strongly against the notion that panic is a reaction to nonspecific distressing stimuli and suggest more specific biological bases. 1983).1% and 5. For example. and of low income increased risk for panic disorder. with a 0. and genetic findings are described in the discussions that follow. Thus. 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.0%.More recently. rates for panic disorder without agoraphobia were 1. we summarize the evidence for or against some of the most promising ones. however. 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. intravenously administrated propranolol. 2006). a regular accompaniment of panic attacks induced in the laboratory (Liebowitz et al. the 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). 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. This nucleus is located in the pons . whether the reaction is specific only to patients with anxiety disorder. Researchers in the 1930s and 1940s did show that epinephrine infusion caused the physical.

Also. and standard benzodiazepines). amygdala. These drugs range from those clearly effective in blocking human panic attacks (e. limbic lobe. TCAs) to those of more dubious efficacy (e.g. in the form of markedly elevated MHPG volatility in response to clonidine challenge. and cerebral cortex. effectively slowing neural transmission. whereas their pH response was not altered. The subjects all believed that these attacks were quite typical of their naturally occurring attacks. 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. which is also reported to increase locus coeruleus firing. 1984). a major noradrenergic metabolite. 1997). propranolol. The possibility is then raised that either aberrant production of an endogenous ligand or altered receptor sensitivity may occur in patients . have suggested noradrenergic dysregulation in panic.. closely resembles such attacks. drugs known to be capable of increasing locus coeruleus discharge in animals are anxiogenic. In a recent study. The results from challenge tests with the 2-adrenergic agonist clonidine. has been described in panic disorder patients and normalizes after treatment with selective serotonin reuptake inhibitors (SSRIs) (Coplan et al. Theories have included nonspecific arousal that cognitively triggers panic. Dysregulated noradrenergic function. which are inverse agonists of this receptor complex. 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. whereas many drugs that curtail locus coeruleus firing and decrease central noradrenergic turnover are antianxiety agents. Lactate-provoked panic is specific to patients with prior spontaneous attacks. 2006). 1984).. of course. Such a finding is suggestive of heightened central noradrenergic activity in panic (Charney et al. panic disorder patients had heightened cardiovascular responses but blunted growth hormone responses to clonidine (Nutt 1989). subjects with panic disorder were found to have greater hypocapnia in response to hyperventilation. However. induction of metabolic alkalosis. morphine. controversy exists about the relevance of these animal models. This would. support the idea that the locus coeruleus is a kind of generator for anxiety attacks. The panicogen sodium lactate Although not without some controversy. and transient intracerebral hypercapnia. Control subjects did not experience panic attacks during the infusion. Binding of a benzodiazepine to the benzodiazepine receptor facilitates the action of GABA.and contains more than 50% of all noradrenergic neurons in the entire central nervous system. is an anxiolytic medication and has not been reported to induce panic. the benzodiazepine receptor is linked to a receptor for the inhibitory neurotransmitter GABA. The mechanism. produces an acute anxiety syndrome when administered to laboratory animals or to normal human volunteers. in patients with frequent panic attacks compared with patients who have panic attacks less frequently or with healthy control subjects. the finding that 10 mL/kg of 0. whereas ablation of the animal locus coeruleus renders an animal less susceptible to fear response in the face of threatening stimuli (Redmond 1979).g. and can be blocked by the same drugs that block natural attacks (Liebowitz et al. that may account for the observed biochemical and physiological changes (Liebowitz et al. Having been replicated on numerous occasions under proper experimental conditions. although difficult to interpret. and TCAs. Examples of medications that curtail locus coeruleus firing are clonidine. implicating exaggerated buffering possibly mediated by increased lactate (Friedman et al. there is no consistent pattern of increased locus coeruleus discharge associated with anxiety in animals. endorphin. sodium lactate provocation of panic attacks has captured a lot of attention as an experimental model for understanding the pathogenesis of spontaneous panic attacks. benzodiazepines have long been known to be a highly efficacious treatment for panic. One series of compounds. buspirone. Yohimbine challenge was reported to induce greater anxiety and a greater increase in plasma 3-methoxy4-hydroxyphenylglycol (MHPG). 1985a) has been subject to much uncertainty and controversy. In humans. including the hippocampus. however. propranolol. the -carbolines.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. clonidine. Compared with control subjects. the locus coeruleus may be involved in arousal and response to novel stimuli rather than in anxiety (Aston-Jones et al. However. 1984). Electrical stimulation of the animal locus coeruleus produces a marked fear and anxiety response. The GABA–benzodiazepine system Another area of inquiry that may relate to the biology of panic is the -aminobutyric acid (GABA)–benzodiazepine receptor complex. with hypersensitivity of some and subsensitivity of other brain 2-adrenoreceptors. hypocalcemia. On the other hand. alteration of the ratio of nicotinamide-adenine dinucleotide (NAD) to the hydrogenated (reduced) form of nicotinamide-adenine dinucleotide (NADH). It sends afferent projections to a wide area of the brain. benzodiazepines.

2000). would clearly be of interest in panic disorder. temporal lobes. The benzodiazepine antagonist flumazenil was found to be panicogenic in panic patients but not in control subjects. compared with healthy control subjects. 1999). In one study. although findings in the literature to date have been to a degree contradictory. 2000). sodium bicarbonate infusion provokes panic attacks in . Similarly. 1989). but not in the actual panic attacks (Hollander et al. 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. 2004). 1996). most prominent in the prefrontal cortex and the insula (Malizia et al. Another radioligand PET study reported significant decreases in serotonin transporter binding in the midbrain. 1990). panic disorder patients. demonstrated less reduced saccadic eye movement velocity in response to diazepam. Hypothalamic-pituitary-adrenal axis The hypothalamic-pituitary-adrenal (HPA) system. These findings could tie in neatly to the current neurocircuitry of fear model of panic. and thalamus in participants with current panic disorder. Similarly. One study found that panic disorder patients. and prefrontal cortex binding was also decreased in those subjects who experienced an attack during the scanning (Bremner et al. HPA findings in panic have been very contradictory and have not consistently supported HPA axis dysregulation in the disorder. 1984).with panic. a serotonin precursor. 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. However. In a magnetic resonance spectroscopy study that measured total occipital cortex GABA levels. There is support for such a theory. and abuse have been described (M. inhibiting excitatory pathways from the cortex and the thalamus (Gorman et al. However. a global decrease in benzodiazepine receptor binding has been found with positron emission tomography (PET). in which increased early life stressful events such as separations. inhibiting corticotropin-releasing factor (CRF) release. inhibiting freeze/flight responses. imaging studies have consistently revealed alterations in this system. More recently. adrenocorticotropic hormone and cortisol responses to CRF challenge were not clearly altered in panic patients compared with healthy subjects (Curtis et al. This finding has been consistently replicated and appears specific to panic disorder (Kent et al. 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. 1995). suggesting that a trait-like abnormality in GABA function may contribute to the pathogenesis of panic (Goddard et al. Another study reported that a 22% reduction in total occipital GABA levels was found in panic subjects compared with control subjects (Goddard et al. In one study. as is known to occur in other anxiety and stress states. Indirect evidence is provided by the high efficacy of serotonin reuptake inhibitors in treating panic. it is widely thought that it may be one of the systems that at least indirectly modulate dysregulated responses in the disorder. compared with healthy control subjects. described later. inhibiting noradrenergic activation. 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 prefrontal cortex play a central role in modulating conditioned fear responses. and possibly directly at the level of the amygdala. The serotonergic system Although the serotonergic system has not been as extensively investigated in panic as other neurochemical systems. 2004). hippocampus. however. 2000). to the hypothalamus. Surprisingly. suggesting hyposensitivity of the benzodiazepine receptor in panic (Roy-Byrne et al. interfering with proper benzodiazepine receptor function and causing their symptoms. 2001a). were found to have a deficient GABA neuronal response after acute oral benzodiazepine administration. suggesting a deficiency in an endogenous anxiolytic ligand or altered benzodiazepine receptor sensitivity in panic (Nutt et al. 2004). to the periaqueductal gray region. There is some evidence for uncoupling of noradrenergic and HPA axis activity in panic disorder patients (Coplan et al. Cortisol responses in lactate-induced panic have suggested HPA axis involvement in anticipatory anxiety. another study of flumazenil responses in panic was negative (Strohle et al. Decreased benzodiazepine receptor binding by single photon emission computed tomography (SPECT) was found in the hippocampus of panic disorder patients. depletion of tryptophan. 1998). 1997). B. which is central to an organism's response to stress. in which the amygdala. Stein et al. 1990). resulted in increased anxiety and carbon dioxide (CO 2)–induced panic attacks in panic patients but not in comparison subjects (Miller et al. losses. 2004). Carbon dioxide hypersensitivity theory Controlled hyperventilation and respiratory alkalosis do not routinely provoke panic attacks in most patients with panic disorder. and this decrease correlated significantly with greater panic symptom severity (Maron et al. 2001). More recently.

noradrenergic. and treatment findings in the disorder coupled with human and animal studies in the neurobiology of conditioned fear responses (Gorman et al. the tendency of panic attacks to occur during high-CO 2 states such as deep non–rapid eye movement sleep. In an interesting study of CO 2 inhalation sensitivity before and after psychotherapy or medication treatment in panic disorder patients. but not during childbirth. inspiratory drive is thought to reflect most directly the brain stem component of respiratory regulation (Gorman et al. Panic is speculated to originate in an abnormally sensitive fear network. such as serotonergic. the hypothalamus and activation of the HPA stress axis. panic disorder patients' tendency to chronically hyperventilate. a hypothesis supported by one study (Coryell et al. 1989). patients manifested greater entropy in baseline respiratory patterns. which is then converted in the periphery to CO 2. There is some evidence that irregular breathing patterns are intrinsic to panic patients and are not influenced by induced hyperventilation or cognitive manipulation. CRF. imaging. 2004). 2000). as one of several pathways that become activated by central excitation of the amygdala. then. a "false suffocation alarm" theory of panic has been formulated (D. in a sense. Indeed. 2001). Gorman et al. 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. This CO 2 then selectively crosses the blood-brain barrier and produces transient cerebral hypercapnia. it causes a reliable dose-dependent increase in rat locus coeruleus firing. such as the locus coeruleus and arousal. Stein et al. dysregulated "cross-talk" between various neurotransmitter systems. whereas objective respiratory physiological responses remained unchanged. . This condition constitutes. suggesting that treatment strengthened higher cortical control over subcortical fear-related circuitry (Gorman et al. and bicarbonate do. and the cortex and cognitive interpretations. CO 2 constitutes the common metabolic product of both lactate and bicarbonate. (2000) argued that brain stem respiratory centers are a secondary mechanism by which panic attack symptoms relating to respiration become manifest. premenstrually. suggesting a brain stem rather than a higher brain level dysregulation (Abelson et al. By what mechanism. during the CO 2 induction procedure. F. 1995b). B. their increased variance in tidal volume during steady-state respiration. Alternatively. such as preexisting pulmonary disease. and there are amygdalar projections to several areas involved in various aspects of the fear response. Klein 1993) that proposes that patients with panic are hypersensitive to CO 2 because they have an overly sensitive brain stem suffocation alarm system. the brain stem and respiratory activation. Thus. The hypercapnia then sets off the brain stem CO 2 chemoreceptors. 2004). may underlie the pathogenesis of panic. Input into the amygdala is modulated by both thalamic input and prefrontal cortical projections. it is proposed that the respiratory brain stem nucleus could not be directly triggered by such a variety of agents (Gorman et al. indicating higher levels of irregularity and complexity in their respiratory function (Caldirola et al. Aberrant respiratory sensitivity to CO 2 may be a familial trait that comprises a risk factor for developing panic disorder. does 5% CO 2 induce panic? When CO 2 is added to inspired air. centered in the amygdala. by acting at different pathways or on neurochemical systems of this network. Thus.patients with panic disorder at a rate comparable with that induced by CO 2 inhalation (Gorman et al. 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. an event otherwise characterized by extreme hyperventilation and potentially catastrophic cognitions. leading to hyperventilation and panic. compared with control subjects. 2000). and their greater irregularities in nocturnal breathing (M. 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. panic disorder patients may have hypersensitive brain stem CO 2 chemoreceptors in their medulla. Neurocircuitry of fear The neurocircuitry of fear model integrates neurochemical. GABAergic. for example. Such a model is of interest because it could account for the generally well-established fact that hyperventilation does not cause panic. and sometimes with relaxation. On the other hand. This theory may be supported by the variety of subtle respiratory dysfunctions that appear to be associated with panic. 2005). In other words. 1988). Infused lactate is metabolized to bicarbonate. it was found that after treatment patients exhibited diminished subjective panic responses. This model is thought to explain why a variety of biologically diverse agents have panicogenic properties. Klein (1993) proposed that such a theory of panic could explain. A recent study of respiratory physiology in panic disorder patients found that. lactate. and others. 2001) but not by another (Pine et al. whereas CO 2. D. the opposite of the hyposensitive suffocation alarm seen in Ondine's curse. a rare illness in which the afflicted are at risk for suffocating in their sleep. F. 2006).

Structural volumetric studies have reported decreased gray matter volumes bilaterally in the putamen of panic disorder participants. Freud started to modify his theory. Another important strategy is to examine genetic influences on behaviorally inhibited temperament. which is a risk factor for anxiety disorders. 1997). revealing significantly higher glucose uptake under resting conditions in the bilateral amygdala. Freud (1895b[1894]/1962) postulated that anxiety stems from the direct physiological transformation of libidinal energy into the somatic symptoms of anxiety. the cholecystokinin gene (Wang et al. 2002. 7q (Cheng et al. 2006). Although the basic tenet that anxiety stemmed from undischarged sexual energy remained the same. 2001). Crowe et al. 1992). (1983) found a morbidity risk for panic disorder of 24. possibly suggesting a stronger genetic component in a familial subtype of the disorder. medulla. He found evidence for this process in the sexual practices and experiences of patients with anxiety. 1998). hippocampus. this was no longer posited to be due to external constraints such as sexual dysfunctions. and 9q (Thorgeirsson et al. There have been a number of preliminary positive studies of putative genetic markers and candidate genes for panic disorder. Such anxiety. Michels et al. 2004). Moderate heritability was also found in a female twin study (Kendler et al. each with minor individual effects. Although an earlier whole-genome scan in 23 panic pedigrees did not yield any evidence of linkage (Knowles et al. 1985. all contribute to panic susceptibility (Maron et al. and cerebellum in panic disorder participants compared with healthy control subjects (Sakai et al. However. suggesting that nongenetic factors also play an important role in the development of the illness. Gelernter et al. 2005). including the X-linked monoamine oxidase-A gene in females (Deckert 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. More lengthy expositions and critiques of the psychoanalytic theories can be referred to by interested readers (see Cooper 1985. 1999). without the mediation of psychic mechanisms. midbrain. Also. He termed such anxiety an "actual neurosis" as opposed to a psychoneurosis. 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. 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. originating from overwhelming instinctual urges. 2004). and the 5-HT2A receptor gene (Inada et al. but not all. In accordance with Freud's developing topographic theory of the mind. A PET functional neuroimaging study supported an amygdala-based fear network in panic. 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). panic and agoraphobia may share some. 2005). 2001). Individuals with an early onset of the disorder appear to have a much higher familial aggregation of the disorder. 2002. Nemiah 1988). 2006). the absolute concordance rate in monozygotic twins was 31%. 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. 2005b). 1999). caudal pons. later genome scan studies have revealed links to chromosomes 7p (Crowe et al.3% among normal control subjects. 2006). There is also evidence of interactions of serotonergic and noradrenergic gene variants in panic disorder (Freitlag et al. of their susceptibility loci (J. the peripheral benzodiazepine receptor gene (Nakamura et al. would today be referred to as id or impulse anxiety. Woo et al. the cholecystokinin receptor gene (Kennedy et al. Freud's first theory of anxiety neurosis (id or impulse anxiety) In his earliest concept of anxiety formation. because of the postulated absence of psychic processes. thalamus. 1998). One study found that in families with panic-disordered parents. Over the next several years. which might better lend itself to molecular genetic studies (Goldstein et al. 13q (Hamilton et al. Hamilton et al. 2005). It is likely that genetic variants of several or multiple candidate genes in different neurotransmitter systems. 2003). 2003).7% among relatives of patients with panic disorder compared with only 2. 2005). and the adenosine 2A receptor gene (Deckert et al. 1998. anxiety resulted from . 2005). which were characterized by disturbed sexual arousal and continence and coitus interruptus. the catechol-O-methyltransferase gene (Hamilton et al. the magnitude of which was associated with panic severity (Yoo et al. again supporting a model of diminished top-down inhibition by prefrontal cortical regions over hypersensitive limbic regions (Kent et al. behavioral inhibition in the offspring was associated with corticotropin-releasing hormone variants (Smoller et al.Neuroimaging studies are implicating these and other areas in the neurocircuitry of panic.

Undischarged libidinal energy was physiologically transformed into anxiety.forbidden sexual drives in the unconscious being repressed by the preconscious. superego prohibitions. Whereas Freud concentrated on the role of sexual impulses and the oedipal conflict in the genesis of 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 . anxiety leads to repression. by their nature or in the patient's prior experience. With the broadening of psychodynamic theory over the decades. 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. For example. or compulsions. they remain an invaluable tool in the understanding and treatment of at least some patients. 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. such as Melanie Klein (1948) and Joachim Flescher (1955). and external reality demands. 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. dangerous. and still others have phobias. 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. Inhibitions and neurotic symptoms develop as measures designed to avoid the dangerous situation and to allow only partial gratification of instinctual wishes. In an attempt to reconcile this unpredictability with classical psychodynamic theory. these theorists drew attention to the role that aggressive impulses and preoedipal dynamics can also play in generating anxiety. anxiety is an affect belonging to the ego and acts as a signal alerting the ego to internal danger. with the advent of the structural theory of the mind. 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. modern biological theories of panic are in many ways more reminiscent of his original physiological formulation. Structural theory and intrapsychic conflict By 1926. This is a succinct description. all of which are accessible in psychodynamic treatment (Shear et al. In the revised theory. Rather. In particular. 1985). Indeed. Although Freud's first model of anxiety was later overshadowed by the conflictual model. it should be pointed out that Freud's theory of anxiety formation is not incompatible with biological theories of anxiety. thus warding off signal anxiety. nothing is ever found but the emotional state of anxiety. Although psychoanalytic theories are not universally accepted by psychiatrists today. he understood them. Since Freud. Early on. According to Freud. instead of the reverse. anxiety over loss of the other's love. Some patients have anxiety attacks. Psychoanalytic theorists after Freud. such as annihilation anxiety. Along these more contemporary lines of thinking. made more than a century ago. and id anxiety. separation anxiety. Alternatively. The danger stems from intrapsychic conflict between instinctual drives from the id. whereas individuals without this neural predisposition may manifest milder forms of signal anxiety (Nemiah 1981). to be manifestations of a physiologically induced tension state. 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. 1993). In the case of agoraphobia we often find the recollection of an anxiety attack. obsessions. like anxiety neurosis. Freud's theory of anxiety had undergone a major transformation (Freud 1926/1959). also made significant contributions to the understanding of the psychodynamic origins of anxiety. Furthermore. 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. others have more chronic forms of anxiety. Freud did not consider phobias to be psychologically mediated. of the development of anticipatory anxiety and agoraphobia following a panic attack. which became attached to and partly discharged through objects that were. The intrapsychic conflict model of anxiety continues to constitute a major tenet of contemporary psychoanalytic theory. 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. At that time. Also. Anxiety acts as a signal to the ego for the mobilization of repression and other defenses to counteract the threat to intrapsychic equilibrium. then. 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. different forms of anxiety have been elaborated. castration anxiety. superego anxiety. Freud (1895a[1894]/1962) also observed that in the analysis of phobias. a psychodynamic study of patients with panic disorder found that in patients who are neurophysiologically predisposed to early fearfulness.

separation anxiety). 2003). the pressing of the lever becomes a conditioned stimulus that precedes the unconditioned stimulus (i. Learning Theories Behavior or learning theorists hold that anxiety is conditioned by the fear of certain environmental stimuli. D. fear of separation from their mothers was usually the basis behind refusing to go to school. we might say that anxiety attacks are conditioned responses to fearful situations. anxiety. whether during vigorous exercise or minor emotional upset.e.psychopathology. skidding in a car during a snowstorm) is paired with the experience of rapid heartbeat (i. were greater in new-onset panic patients than in control subjects (Faravelli and Pallanti 1989).e. rapid heartbeat alone. The anxiety may persist even after the child is old enough to feed him. the conditioned response). Indeed. D. and thus the infant learns to become anxious automatically whenever the mother is absent (i.g. This may occur if the retrospective histories of a lesser degree of separation anxiety in patients with panic attacks alone are misremembered. that leads the animal to avoid contact with the lever.. However. Thus. On the other hand.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. becomes . and separation anxiety is linked to agoraphobia. in response. Gittelman-Klein and Klein (1971) conducted a study of imipramine treatment for children with school phobia. the conditioned stimulus) and tremendous anxiety. the unconditioned stimulus). but this could be related to their young age. especially events related to loss. 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. F. Based on Bowlby's (1973) work on attachment and separation. so that although psychological triggers for anxiety may still be found. Hypothesizing a link between adult panic attacks and childhood separation anxiety. thereby avoiding the shock. 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. 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. 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. then why is imipramine effective in the treatment of school phobia? On the other hand.e. reinforces the avoidant behavior.or herself. 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. the conditioned stimulus). 1985). have claimed that this neurophysiological and ethological model of a disrupted separation mechanism and panic may be unnecessarily reductionistic (Michels et al. 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. often taking the form of school phobia. 20%–50% of adults with panic disorder and agoraphobia recall manifesting symptoms of pathological separation anxiety. The drug proved successful in getting the children to return to school. In the early 1960s. In these children. Perhaps both panic disorder and panic disorder with agoraphobia are linked to a biologically disordered separation mechanism that is responsive to imipramine.. an infant learns that if his or her mother is not present (i. This is further confirmation of the link between separation anxiety and panic attacks. called "distress vocalizations. This leads to a decrease in anxiety level. F. Successful avoidance of the unconditioned stimulus..e. children with school phobia do not have spontaneous panic attacks." 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. For example. One systematic study has shown that the number and severity of recent life events. Infant animals demonstrate their anxiety when separated from the mother by a series of high-pitched cries. To give another example. he or she will suffer hunger (i. Furthermore. when they were children. Long after the accident.. the shock). Is early separation anxiety linked to agoraphobia and to panic attacks per se? If imipramine affects panic attacks.e.. By analogy with this animal model. If every time a laboratory animal presses a bar it receives a noxious electric shock. a life-threatening situation in someone's life (e. Contemporary psychoanalysts. The conditioned stimulus releases a conditioned response in the animal.. 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). 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..

. Such patients require other forms of intervention. there were several predictors of poorer outcome. Another long-term outcome study over a 5-year period had . So even though learning theories have a powerful basis in experimental animal research. Course and prognosis of panic disorder Course Variable. or life-threatening events. cocaine intoxication. and Mortality The course of illness without treatment is highly variable and is summarized in Table 12–5. such as altered functioning of the amygdala and related fear circuits (discussed earlier).g. high interpersonal sensitivity. At the extreme. they do not seem to explain adequately. only to be followed months to years later by a new outburst. exposure to childhood physical and sexual abuse was associated with increased risk of later panic attacks and disorder. 50% have limited impairment. However. Traumatic Antecedents Childhood interpersonal trauma also appears to make a contribution to the likelihood that individuals will manifest panic disorder. Of note. often leads to complete remission. for many patients no such traumatic event can ever be located. including greater severity of panic attacks and agoraphobia. death. do seem to be paired with the onset of panic disorder. 2005). Clinical experience does not support that anxiety disorder patients undergo repeated traumatic events. Even years into the illness. examination of trauma rates in the National Comorbidity Survey community sample. Prognosis. However. Course. 2002).capable by itself of provoking the conditioned response of an anxiety attack. Exposure to interparental violence was not a factor (Goodwin et al. A 7-year follow-up study examined prognostic factors in naturalistically treated patients with panic disorder. after disaggregating the impact of comorbid PTSD. and therefore they should be able to extinguish their anxiety. a substantial number of patients with significant phobic avoidance remain anxious and frightened of confronting feared situations even after the attacks have been blocked. such as thyroid disease. divorce) High interpersonal sensitivity Single marital status At present. heightened anxiety responses could conceivably persist over time. In a large prospective birth cohort studied to the age of 21 years. Similarly. longer duration of illness. significantly more than in psychiatric comparison subjects (Bouwer and Stein 1997). for example. Although patients had generally good outcomes. Certain problems are posed by such a theory. described elsewhere in this chapter. found that 24% of females and 5% of males with panic disorder reported histories of sexual molestation. typically with periods of exacerbations and remissions Outcome About 33% recover. Treatment aimed at blocking the occurrence of the attacks. coupled with a dysregulated biological mechanism or vulnerability that may be linked to the process of fear conditioning in panic. however. The illness seems to have a waxing and waning course in which spontaneous recovery occurs. described in detail later. 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. there is no reliable way to know which patient will develop. although some traumatic situations. before phobic avoidance has become an ingrained way of life. severe traumatic events during childhood and unfavorable parental attitudes were associated with panic disorder (Bandelow et al. effective disruption of the attacks with medication can lead to resolution of anticipatory anxiety and phobias without other treatment. traumatic suffocation incidents have been found in about 20% of panic patients. separation from a parent by death or divorce. comorbid major depression. suggesting the latter could be one risk factor for developing panic disorder (Leskin and Sheikh 2002). such as a suffocation incident. the pathogenesis of human anxiety disorders. and single marital status (Noyes et al. First. is appropriate at any point in the course of the illness when such attacks are occurring. TABLE 12–5. even after adjusting for prospectively assessed confounding factors. low social class. Pharmacological blockade of panic attacks early in the illness. some patients become completely housebound for decades. agoraphobia. 1993). Morbidity. Results are often dramatic. In a clinical cross-sectional study comparing panic disorder and psychiatrically healthy subjects. in and of themselves.

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. the most significant predictor of poor outcome was an anxious-fearful personality type. however. in a reanalysis of the ECA data controlling for all comorbidity rather than one disorder at a time. 1995). Similarly. Epidemiological data further supported this finding in the ECA study. longitudinal. The one cardiovascular abnormality that has been found to occur at a higher rate in patients with panic disorder is mitral valve prolapse. such medical risks are not routinely evident to clinicians in the usual status of patients undergoing treatment for panic disorder. An increased death rate from cardiovascular illness in panic disorder was partly supported in an epidemiological investigation by Weissman et al. One other possible explanation for increased cardiovascular/cerebrovascular risk in patients with panic disorder may be related to aspects of their lifestyle.fairly optimistic findings: 34% of patients were recovered. However. 2000). (1990). posttraumatic stress. naturalistic study reported that. 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. 46% were minimally impaired. psychosis) . panic disorder patients had a significantly higher risk for strokes than did patients with other psychiatric disorders. mitral valve prolapse itself is rarely a cause of premature death or major morbidity. TABLE 12–6. 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. whereas longer duration of illness and more severe initial avoidance were unfavorable predictors (Katschnig et al. the likelihood of panic disorder remission was not affected by comorbid personality disorders (Massion et al. where the lifetime rate of suicide attempts in persons with uncomplicated panic disorder was 7%.9% rate for uncomplicated major depression (J. reanalysis of the National Comorbidity Survey data revealed that in the absence of comorbidity. these diagnoses are not always obvious. Most such patients have normal medical workups. followed by poor response to initial treatment (O'Rourke et al. although several methodological limitations were identified. 2002). in contrast to GAD and social phobia. Of note. Alternatively. and 20% remained moderately to severely impaired. leading them to avoid exertion of any kind. in addition to the presence of at least four physical symptoms. and continuous use of medication were not related to outcome. initial medication. Such patients tend to live relatively sedentary lives. left ventricular enlargement and increased risk of thromboembolic events have also been contemplated to account for the association (Weissman et al. panic disorder responders were not at heightened risk of self-reported suicide attempts (Vickers and McNally 2004). 1996). Panic attack frequency at baseline. 1990). However. In this study. 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. about the same as the 7. these attacks are not secondary to a known organic factor or due to another mental disorder. Heavy cigarette smoking. Finally. A recent 5-year prospective. and a number of other psychiatric and medical disorders may mimic these conditions (Table 12–6). Finally. 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. The impact of comorbidity is another important consideration in assessing prognosis. 1990). Johnson et al. This association could conceivably explain a higher incidence of cardiovascular-related death in patients with panic disorder. These panic attacks are characterized by a sudden crescendo of anxiety and fearfulness. Finally. an association between panic and suicide attempts could no longer be shown (Hornig and McNally 1995). and some report that vigorous physical exercise precipitates their panic attacks. alcoholism. another large outcome study showed that less than 20% of panic disorder patients remained seriously agoraphobic or disabled. paranoia. and poor diets could also contribute to an increased risk in panic patients.

routinely become demoralized as the impact of the illness progressively restricts their ability to enjoy a normal life. Unlike panic disorder patients. Although agoraphobic patients are frequently afraid that they are going crazy. such as a fear of being or of traveling alone after an assault. With regard to the agoraphobic component of the disorder. By far the most problematic is the differentiation of primary anxiety disorder from depression. with anxiety symptoms coming later. such as sedatives. Psychotic states can be differentiated from agoraphobia by the presence of delusions. and thought process disorder. somatizing patients present with physical problems that do not usually occur in episodic attacks but are virtually constant. However. Patients with depression often manifest signs of anxiety and may even have frank panic attacks. On the other hand. psychotic illness is not an outcome of anxiety disorder. then becoming gradually more disgusted with life. Patients with depersonalization disorder have episodes of derealization/depersonalization without the other symptoms of a panic attack. Patients with panic disorder generally do not demonstrate the full range of vegetative symptoms seen in depression. and then feeling depressed. Reassuring the patient on this point is often the first step in a successful treatment.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. A few other psychiatric conditions often need to be differentiated from panic disorder. patients usually experience dysphoria first. Although patients with panic disorder often fear they will lose their minds or go crazy. widespread fears and avoidance of being alone or of leaving home can also be seen in paranoid and psychotic states. and major depressive disorders. studies have shown that patients with anxiety disorder have increased family history of affective disorder. anxious patients usually have trouble falling asleep—not early morning awakening—and do not lose their appetite. anxiety symptoms usually precede any seriously altered mood. Patients with somatization disorder complain of a variety of physical ailments and discomforts. In cases of panic disorder. Further complicating the picture is the fact that some. Patients can generally recall having anxiety attacks first. several points are helpful. Diurnal mood fluctuation is uncommon in anxiety disorder. PTSD. Although the differentiation of anxiety from depression can at times strain even the most experienced clinician. . they do not exhibit psychotic symptomatology. The order of developing symptoms also differentiates depression from anxiety. However. panic disorder can be complicated by secondary major depression or vice versa. 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). none of which are substantiated by physical or laboratory findings. Patients with PTSD have a typical history of trauma. 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. in attempts at self-medication. panic attacks not infrequently involve depersonalization and derealization as prominent symptoms. if untreated for significant amounts of time. Thus. In depression. psychiatric conditions that involve pathological anxiety can make the differential diagnosis of panic disorder difficult. but not all. patients with panic disorder. In one study. hallucinations. These patients did not resume alcohol consumption once their panic attacks were eliminated. Undoubtedly some patients with anxiety disorders abuse alcohol and drugs.

For this reason. usually does not reveal further vegetative symptoms or a loss of pleasure or interest in activities. are rare in agoraphobia. It should be remembered. 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. extreme low energy. Close questioning. 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. chest pain. Patients with atypical depression and a history of panic attacks may respond preferentially to monoamine oxidase inhibitors (MAOIs. Patients with atypical depression (i. Agoraphobic individuals will usually say they would love to leave home and engage in a variety of activities.The distinction between depressive disorders and agoraphobia is more difficult. lightheadedness. so that even when the apparently primary thyroid disease is corrected. and depressed but reactive mood) frequently have panic attacks but rarely have agoraphobia as part of their life history or current symptomatology. Liebowitz et al. Cardiac disease The relationship of mitral valve prolapse to panic disorder has attracted a great deal of attention over the years. A comparison of symptoms in mitral valve prolapse and panic disorder is provided in Table 12–7.and hypothyroidism can present with anxiety unaccompanied by other signs or symptoms.. panic attacks may continue until specifically treated. actually causes mitral valve prolapse (Mattes 1981). In contrast. A meta-analytic study of 21 studies found that there does appear to be a significant association between panic disorder and mitral valve prolapse. it is imperative that all patients complaining of anxiety undergo routine thyroid function tests. Early morning awakening and pervasive anhedonia. depressed individuals usually see no point in going out because nothing gives them any pleasure. however. 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 – ++ ++ + – ++ ++ ++ ++ ++ . by creating intermittent states of high circulating catecholamine levels and tachycardia. depression characterized by hypersomnia. 1981). however. and they believe that people will be better off without them. Patients with agoraphobia are frequently demoralized and will state that they feel depressed. TABLE 12–7. although the possibility of publication bias favoring positive reports cannot be ruled out (Katerndahl 1993). including the evaluation of the level of thyroid-stimulating hormone. screening of patients known to have mitral valve prolapse reveals no greater frequency of panic disorder than is found in the overall population.e. Others have suggested that panic disorder. 1981). and patients with both mitral valve prolapse and panic disorder are just as sensitive to sodium lactate as are those with panic disorder alone. However. Although patients with mitral valve prolapse occasionally complain of palpitations. that thyroid disease can act as one of the predisposing triggers to panic disorder. Treatment for panic attacks works regardless of the presence of the prolapsed valve. Panic patients with and without mitral valve prolapse are similar in several important ways. Hyperthyroidism and hypothyroidism Both hyper. Both groups commonly experience spontaneous panic attacks. if only they could be sure of not panicking. 1985b). which are common symptoms in endogenous depression. and fatigue. hyperphagia. There are reports that mitral valve prolapse might go away if the panic disorder is controlled (Gorman et al. symptoms of a full-blown panic attack are rare.

there is no scientific proof at present that this is ever a cause of any psychiatric disturbance. a speedy feeling. should be ruled out by electrocardiography. going crazy. Otolaryngology consultation is warranted when this condition is suspected. What it may tell us about the underlying etiology of panic disorder is a question currently under vigorous investigation. For patients with severe anxiety. and insomnia. it can be helpful to initially prescribe a concomitant benzodiazepine that can be gradually tapered and discontinued after several weeks of antidepressant treatment. it is strongly recommended that patients with panic disorder be started on lower dosages of antidepressants than would be given to depressed patients. and anxiety that mimic panic attacks. If this condition is suspected. During an active phase. Also importantly. especially paroxysmal atrial tachycardia. Glucose tolerance tests are not helpful in establishing hypoglycemia as the cause of anxiety. whether TCAs or serotonin reuptake inhibitors. the diagnosis is made by collection of urine for 24 hours for determination of catecholamine metabolite concentration. Rather than merely feeling dizzy. losing control Mitral valve prolapse – – – Panic disorder ++ ++ ++ Note. the patient complains prominently of chest pain. warranting a serum calcium level before definitive diagnosis is made. Disease of the vestibular nerve can cause episodic bouts of vertigo. Therefore. + = occasionally. Whether they are a distinct subgroup with definite neurological abnormalities is currently under study. Although this is usually transient. ++ = often present. tremulousness. Pheochromocytoma is a rare. and a summary of the pharmacological treatment of panic disorder is . Therefore. – = rarely present. Studies with insulin tolerance tests in panic disorder have yielded negative results. In any event. usually benign tumor of the adrenal medulla that secretes catecholamines in episodic bursts. Although many patients believe that their anxiety disorder is caused by reactive hypoglycemia. Several classes of medications have been shown to be effective in accomplishing this goal. merely finding a normal blood pressure does not rule out a pheochromocytoma. Other medical illnesses Hyperparathyroidism occasionally presents as anxiety symptoms. although in most cases. agitation. The central feature in the treatment of panic disorder is the pharmacological blockade of the spontaneous panic attacks. and anxiety.Symptoms Fainting Trembling Fear of dying. the patient characteristically experiences flushing. Blood pressure is usually elevated during the active phase of catecholamine secretion but not at other times. In a study of patients with confirmed pheochromocytoma. Some panic patients primarily complain of dizziness or unsteadiness. 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. nausea. because they did not experience terror during the attacks and did not develop anticipatory anxiety or agoraphobia (Starkman et al. 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. Treatment Pharmacotherapy Antidepressants When initiating a drug regimen for a patient with panic disorder. it is one of the main reasons why patients unfortunately opt to discontinue medication early on. 1990). lightheadedness. some patients with panic disorder display an initial hypersensitivity to antidepressants. because up to 40% of the normal population has a random low blood-sugar level during a routine glucose tolerance test. at least initially. or palpitations. during which they complain of jitteriness. skipped beats. 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. Ischemic heart disease and arrhythmias. such patients often experience true vertigo in which the room seems to spin in one direction during each attack. A variety of cardiac conditions can initially present as anxiety symptoms. but none had panic disorder. about half met criteria for the physical symptoms of panic attacks.

Most patients need at least 150 mg daily of TCAs. the most widely studied and used medications in the past were the TCAs. Imipramine: well studied Clomipramine: high efficacy but not easily tolerated Desipramine: if low tolerance to anticholinergic side effects Nortriptyline: if prone to orthostatic hypotension. Other TCAs. 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. Food and Drug Administration. Historically. Start with very low dosages and increase. Because 50 mg is usually inadequate for full panic blockade. such as desipramine. and social phobia. Clonazepam: longer-acting. escitalopram: similarly efficacious Venlafaxine extended-release: FDA approved Tricyclic antidepressants General indications: Established efficacy. Pharmacological treatment of panic disorder Selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors General indications: First-line. 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. less withdrawal. depression. and given their several advantages over TCAs they have become the first-line treatment for panic. initial treatment phase until antidepressant begins to work. SSRIs = selective serotonin reuptake inhibitors. and clomipramine. . Panic patients not responding to high dosages of imipramine should have blood TCA levels measured. newer antidepressants. 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.S. The presence of depressed mood is not a predictor or requirement for this class of medications to be effective in blocking panic attacks. Phenelzine: most studied Tranylcypromine: less sedation High-potency benzodiazepines General indications: Poor response or tolerance of antidepressants. second line if SSRIs fail or are not tolerated. F. TABLE 12–8. On "high" imipramine dosing of around 200 mg/day. 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. fluoxetine. Klein 1964. prominent anticipatory anxiety or phobic avoidance. Also first choice with comorbid obsessivecompulsive disorder. have also been found effective. In some cases. FDA = U. generalized anxiety disorder. although they have not been studied as extensively as imipramine. not well tested to date. 1986b). a dosage of imipramine of more than 300 mg is necessary. nortriptyline.presented in Table 12–8. especially imipramine (D. At present. underdosage commonly occurs. Mavissakalian and Michelson 1986a. 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. have been shown to be efficacious in treating panic. citalopram. TCAs are now reserved for patients who do not have a good response to. paroxetine: FDA approved Fluvoxamine. in particular the SSRIs. Sertraline. newer antidepressants. response seen with low to moderate dosages. comorbid atypical depression or social phobia. and unfortunately. The dosage can be given all at once. or do not tolerate. less frequent dosing. alone or in combination with benzodiazepines if needed.

however. blood levels will be disproportionately low for the dosage. 2001). 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.Often. or proportion of patients free of panic attacks at endpoint. 1998. 1998). with an 11% dropout rate due to adverse events (Sheehan et al. Fluoxetine. and OCD. In a 1-year controlled maintenance extension of the same study. Patients who experience excessive anticholinergic side effects to imipramine can be given desipramine instead. whereas the 10-mg and 20-mg dosages did not. 1998). Another SSRI. social phobia. the initial responders to acute fluoxetine treatment demonstrated significant further improvement if randomized to fluoxetine and significant worsening if randomized to placebo (D. such as depression. and impairment than to panic attacks per se. citalopram. paroxetine. whereas the middle dosage of 20–30 mg daily again showed the best response (Lepola et al. 1995). using a flexible dosage range of 75–225 mg/day for 10 weeks. or noncompliance. reported better response and remission rates than placebo with a greater improvement in number of panic attacks. Another study showed that both escitalopram and citalopram were comparably superior to placebo in treating panic disorder symptoms and severity. Over a 6-month maintenance treatment period. 1999). and high dosages are generally not needed and less tolerated. and paroxetine controlled-release was well tolerated. The efficacy of paroxetine has been demonstrated at dosages of 20–60 mg daily (Oehrberg et al. Like the TCAs. Food and Drug Administration (FDA)–approved SSRIs for this indication. depressive symptoms. anxiety. Pohl et al. 1998). The SSRI sertraline has also been found to be efficacious in treating panic disorder in large controlled trials (Londborg et al. they comprise the first line in the treatment of panic disorder. anticipatory . SSRIs can cause uncomfortable overstimulation in panic patients if started at the usual dosages. especially at a dosage of 20 mg/day rather than 10 mg/day. 1998). A number of controlled treatment trials have now shown that the potent serotonin reuptake blockers are highly effective in the treatment of panic. tolerability. as in the trials just described. A large multisite placebo-controlled trial of venlafaxine extended-release in 361 adult patients. As a first-line treatment. 100. and escitalopram had a low discontinuation rate of 6% (Stahl et al. they also offer the advantage that they are effective for several of the commonly comorbid disorders. all SSRIs have comparable efficacy in treating panic. 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. A prior history of benzodiazepine use did not appear to affect the tolerability or response to sertraline treatment. A moderate or lower daily dosage is usually adequate for most patients. anxiety. there was no difference among three sertraline dosages of 50. highlighting the importance of trying higher dosages if response to lower dosages is inadequate (Ballenger et al. Fluvoxamine at dosages of up to 150 mg/day was reported efficacious in a large controlled trial (Asnis et al. highlighting the importance of looking at the larger picture when assessing change. either alone or in combination with benzodiazepine when needed. 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. The dosage can then be gradually increased to an average dosage through weekly adjustments. 2004). 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. In another study. was also shown to be superior to placebo in the acute treatment of panic disorder (D. the lowest dosage of 10–15 mg was not better than placebo. depression. 2005). Michelson et al. Venlafaxine is also effective in treating panic disorder. suggesting rapid metabolism or excretion. Although paroxetine and sertraline are the only U. or 200 mg daily in reducing panic attacks (Londborg et al. Given their higher safety. 2000).S. 1997). The elderly or patients who are otherwise very sensitive to orthostatic hypotension can be tried on nortriptyline. only the 40-mg daily dosage of paroxetine reached statistically significant superiority over placebo during a 10-week period. Several controlled trials have documented the efficacy of SSRIs in treating panic disorder. 2002). Michelson et al. GAD. malabsorption. It is therefore suggested that treatment be started gingerly at 5–10 mg/day for fluoxetine. dropout rate was significantly lower in those treated with SSRIs (18%) versus TCAs (31%) (Bakker et al. regardless of whether the response to the benzodiazepine had been good or bad (Rapaport et al. agoraphobic avoidance. and ease of administration compared with TCAs. 2003). this study used a wide range of measures and demonstrated that global improvement was more related to phobia. and citalopram and 25 mg/day for sertraline and fluvoxamine. 1998). 2001). 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.

2005). 2003). MAOIs may be an appropriate earlier choice for treatment if SSRIs do not confer adequate results. Long-term efficacy. a very high relapse rate for panic was found when imipramine was discontinued after 6 months of acute treatment. patients were tapered off medication over 4 weeks. high-potency benzodiazepines are also highly effective in treating the condition. 3. 1988). 27% experienced rebound panic attacks. complete agreement has not been reached regarding the recommended course of treatment. tranylcypromine may be tried. After 8 weeks of acute treatment. The disorder can probably best be characterized as chronic. This finding has not yet been replicated in a controlled trial. 82% of patients treated acutely with alprazolam showed at least moderate improvement in panic compared with 43% given placebo. in ameliorating the associated anticipatory anxiety and phobic avoidance. starting at 10 mg in the morning and increasing by 10 mg every 4 days to a maximum of 80 mg daily. 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. the clinician may attempt gradual dosage decreases every few months. After discontinuation. Phenelzine can be started at 15 mg daily in the morning. Although one small open trial reported significant improvement in panic using bupropion (Simon et al. a reasonable recommendation in treating panic patients is to keep them on full-dosage medication for at least 6 months to prevent early relapse. 2001b). fear. MAOIs are equally as effective as the TCAs and the SSRIs in treating panic. MAOIs are an option to consider for patients who fail to tolerate or to respond well to other antidepressants. Benzodiazepines Although clinicians prefer to use antidepressants for the first-line treatment of panic. For patients with severe acute distress and disability who may require immediate relief. In patients with concomitant atypical depression or social phobia. 1997). the duration of required treatment in order to prevent relapse is a function of the natural course of panic disorder. with an exacerbating and remitting course. although treatment outcome and dropout rates did not differ by the end of the trial (Goddard et al. and the lower dosages of 1–2 mg/day were better tolerated. However. However. with significant improvement occurring in the first couple weeks of treatment. and 35% had withdrawal symptoms. Subsequently. Clonazepam appears equally promising in the acute treatment of panic. Thus. Furthermore. The dosage is then increased by 15 mg every 4–7 days as tolerated. If sedation or weight gain is of concern. . as long as the improvement is maintained. 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). Some patients may eventually be able to completely stop medications.0 mg/day or higher (2. Both phenelzine and tranylcypromine successfully treat panic. controlled data and clinical lore do not support its use. according to a large multicenter trial (Rosenbaum et al. Naturalistic follow-up studies of long-term benzodiazepine treatment appear generally optimistic. dependence. up to a maximum of 60–90 mg daily. Full remission of panic attacks with antidepressants usually requires 4–12 weeks of treatment. and reach a minimal dosage on which the patient is relatively symptom-free. Onset of response was rapid. the general treatment principle is that anxiolytics should be reserved until the different classes of antidepressants have failed. and withdrawal. A double-blind study that examined early coadministration of clonazepam (4 weeks. coupled with a very low 6% discontinuation rate (Sarchiapone et al. whereas others will not. These medications have fewer initial side effects than TCAs and serotonin reuptake inhibitors. because most patients maintain their therapeutic gains without increasing their benzodiazepine dosage over time. at least initially. although phenelzine has been studied more extensively. However. In one study. and difficulties in discontinuing the medication are the main areas of concern when choosing benzodiazepine treatment.5 mg/day was least efficacious. and avoidance (Bradwejn et al. and the mean final dosage was 5. and this may be another indication for their initial use. it may be indicated to start with a benzodiazepine and then replace it with an antidepressant. In a controlled prospective study. In the acute treatment of panic attacks. 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. 2003). and 4 mg/day) were equally efficacious. panic outcome for the alprazolam-treated group was not significantly different from that for the placebo group (Pecknold et al.anxiety. Afterward. because they do pose some risk of tolerance.7 mg/day. but dosages of 1. patients can be tapered to half-dosage medication and be followed to ensure that clinical improvement is maintained. Therefore. 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. patients who do not respond to a TCA or a serotonin reuptake inhibitor alone may respond to a combination of the two. Subsequently. possible tolerance and dependency. the lowest dosage of 0.

A fairly large controlled trial of another mood stabilizer. usually to a maximum dosage of 4 mg/day. with side effects limited mainly to sedation. Alprazolam is usually started at 0.600 mg daily. Other medications Buspirone is a 5-HT1A agonist.Clonazepam should generally be preferred as a first choice. 1993). In one open trial.5 mg bid and increased only if needed. 1993). an intracellular second messenger precursor. 1995. Valproic acid may also have some beneficial effects in the treatment of panic attacks (Keck et al. a trial of -blockers would be indicated. have not been reported. When response to SSRIs and other antidepressants has been inadequate. plus a number of bothersome side effects. makes clonidine a poor initial choice for treatment of panic disorder. such as public speaking. Psychotherapy Psychodynamic psychotherapy . However. This loss of response. the strongest predictor of taper failure was initial severity of panic attacks rather than alprazolam dosage (Rickels et al. 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. Inositol.5 mg three times a day (Hirschmann et al. Treatment of at least 6 months is recommended. showed it to be no better than placebo in treating panic disorder (Pande et al. although a post hoc analysis showed it to have some efficacy in the more severely symptomatic patients. Although benzodiazepines are generally safe. which inhibits locus coeruleus discharge. Atypical antipsychotics have also received attention in recent years. 2006). Spiegel et al. there is no evidence that -adrenergic–blocking drugs. 2005). one controlled study found clonidine to be efficacious for both panic disorder and GAD (Hoehn-Saric et al. 1994). at flexible dosages of 600–3. all 12 patients were moderately to markedly improved after 6 weeks of treatment. would seem for theoretical reasons to be a good antipanic drug. If panic attacks occur in a specific social context. such as propranolol. there is a concern that some patients may become tolerant or even addicted to these medications. resulting in 82% of patients rated as responders by the end of the trial (Sepede et al. 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. 1993). It should generally be started at 0. 2000). In a controlled study. as with the antidepressants. However. 2000).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. Discontinuation must be gradual to prevent withdrawal: 15% of the total dosage weekly is generally a safe regimen. 2001). are effective in blocking spontaneous panic attacks. gabapentin. 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. Clonidine. and 11 continued the medication and maintained their gains after 6 months (Woodman and Noyes 1994). and clonazepam may cause depression. Controlled trials. Palatnik et al. Similarly. Although some patients may initially respond to clonidine. Similarly. but an even slower rate may be required to prevent the recurrence of panic. 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. 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. because alprazolam may occasionally cause mania. 1993. Patients' moods must be followed. however. has been reported to have some efficacy in treating panic disorder in two small double-blind. 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. one-third of patients were unable to tolerate a 4-week taper off alprazolam after 8 months of maintenance treatment. controlled 4 week trials at a dosage of 12–18 g/day (Benjamin et al. suggesting that an augmentation study in refractory panic might be worthwhile. nonbenzodiazepine antianxiety agent and has not been found effective in treating panic. one augmentation strategy shown to be effective in a small blinded trial may be to add pindolol at 2. In one study. the therapeutic effect tends to be lost in a matter of weeks due to receptor habituation.

Yet supportive psychotherapy alone is not an effective enough treatment for panic disorder. insistence on dynamic understanding and on responsibility for one's symptoms may. Cognitive-behavioral therapy CBTs have long focused on phobic avoidance. Cognitive treatment of panic involves cognitive . leading to further damage in self-esteem and strengthened masochistic defenses. and emphasized the need for further and controlled studies (Milrod et al. 2000). a subgroup of panic patients remain wary of independence and assertiveness. Supportive psychotherapy and education about the illness are necessary to urge the patient to confront the phobic situation. exposure to somatic cues. 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. in the long run. suggesting that psychodynamic therapy may be an important additional treatment for at least some patients with panic. but more recently the techniques have been developed and shown to be effective for panic attacks. Supportive psychotherapy Despite adequate treatment of panic attacks with medication. usually involving a hierarchy of exposure to feared sensations through imaginal and behavioral exercises. interest in CBT for panic has surged. at least in the selected sample. it is also clear that there are case reports of patients who were successfully treated for panic with psychodynamic therapy or psychoanalysis. Significant unconscious conflict over separations during childhood sometimes appears to operate in patients with panic disorder. 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. However. depression. 2001). and overall impairment. to control both acute and chronic hyperventilation. 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. TABLE 12–9. Encouragement from other patients with similar conditions is often quite helpful. either dynamic or behavioral. An open trial of psychodynamic monotherapy in panic disorder documented clear efficacy for this modality. traditional psychodynamic psychotherapy might be helpful for some of these patients. Pharmacotherapy is in no way incompatible with behavioral or psychodynamic treatment for patients with panic disorder. The study included 14 patients with panic disorder who were treated for 12 weeks with twice-weekly psychodynamic psychotherapy alone. Cooper (1985) emphasized that in patients with a predominant biological component to their illness. 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). In addition to supportive and behavioral treatment.Even after medication has blocked the actual panic attacks. leading to a reemergence of anxiety symptoms in adult life each time a new separation is imagined or threatened. Patients who fail to respond may then need additional psychotherapy. 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). 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). be not only useless but potentially harmful. In recent years. and symptomatic gains were maintained over a 6-month follow-up (Milrod et al. Systematic studies examining the efficacy of psychodynamically oriented psychotherapy in panic disorder are few but promising. anxiety. Furthermore. successful psychotherapy often cannot take place until the more debilitating aspects of these syndromes have been eliminated pharmacologically. phobic avoidance may remain. and relaxation training. Results showed significant improvement in panic. there were 16 responders out of 21 patients treated with panic-focused psychodynamic psychotherapy. Indeed. 1990). In the completed report of these open trials.

with 23% experiencing relapse at some time during follow-up. medication alone is often not adequate treatment in patients with significant agoraphobic avoidance. M. such as psychoeducation. especially with combined cognitive restructuring and exposure. In a primary care setting. 2001). after the initiation of medication treatment for initial symptom control. 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. Michelson et al. 2004). 1995.restructuring. anxiety.. on the whole. 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. 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. the addition of adjunctive SSRI treatment can be beneficial (Kampman et al. However. so as to give the uncomfortable affects and physical sensations associated with panic a more benign interpretation. A more middle-of-the-road view is that panic patients do have extreme physical sensations. 93% were in remission after 2 years and 62% after 10 years (Fava et al. 1983. and imipramine to be similarly effective. Similarly. it is generally accepted that some means of exposing agoraphobic patients to the feared situations is necessary for overall improvement. In a large controlled study of alprazolam plus exposure in patients with panic and agoraphobia. 2006). and only early improvement in avoidance predicted global improvement after treatment (Basoglu et al. it was found that when patients had an illusion of control over the inhaled mixture. 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. 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. Several studies have shown that these various cognitive and behavioral techniques are successful in the treatment of panic disorder (Barlow et al. more successful than nonspecific techniques in reducing agoraphobic avoidance.g. 1994). whereas others have shown imipramine alone to decrease phobic avoidance (Mavissakalian and Perel 1995). such as bursts of tachycardia. the addition of CBT . focused CBT is. 1992. Most studies. In another study. The pure cognitive view is that panic attacks consist of normal physical sensations (e. and a control group and reported comparable high efficacy for all three active-treatment groups. 1994). Another study compared in vivo exposure. However. relaxation. and avoidance were found to be largely independent of each other. 2002). Some studies have not found imipramine to have a significant effect on agoraphobia when given alone or with anti-exposure instructions (Marks et al. Ost and Westling 1995). and supportive therapy. These techniques can be administered in various combinations. Antipanic medication is given to block the occurrence of panic attacks. Beck et al. 1986). there is evidence that in patients who do not benefit adequately from cognitive therapy alone. 2001b). Salkovskis et al. and cognitive therapy had more lasting effects at 9-month follow-up after treatment was discontinued (D. 1990. they experienced significantly fewer and less severe attacks and had less catastrophic cognitions. In addition. 1980). reassurance. interoceptive exposure. Clark et al. 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. 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. palpitations. combination of the two exposures. Findings on long-term outcome of panic with CBT appear to be favorable. with an average 60% improvement after 10 weeks of acute treatment and 77% improvement at follow-up 1 year later (Ito et al. L. the improvements in attacks. a study comparing cognitive therapy to interoceptive exposure found similar efficacy (Arntz 2002). One controlled study found cognitive therapy. 1989." Such a theory has received experimental validation: Sanderson et al. 1993). slight dizziness) to which panic disorder patients grossly overreact with catastrophic cognitions. Conversely. Telch et al. there was evidence of lasting relief for the majority of patients for up to a decade after treatment. and its efficacy in this regard is well documented. This may be achieved through various nonspecific methods. however. 1985). Zitrin et al. 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. 2002). Telch et al. the introduction of CBT greatly increased the likelihood that a patient would be able to successfully taper off medication (Otto et al. (1989) provoked panic attacks in panic disorder patients using CO 2 inhalation. Mavissakalian and Michelson 1986a. 1985. In a study examining the long-term outcome of panic disorder with agoraphobia in a group of 200 patients initially treated with exposure therapy.

worry. and the cumbersome somatic symptom list from the DSM-III-R was simplified (Table 12–10). 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). DSM-IV-TR also clarified that the diagnosis of GAD is excluded when occurring exclusively in relation to other major Axis I disorders. hyperthyroidism) and does not occur exclusively during a mood disorder. occurring more days than not for at least 6 months. TABLE 12–10. The person finds it difficult to control the worry. about a number of events or activities (such as work or school performance). and the anxiety and worry do not occur exclusively during posttraumatic stress disorder. The essential feature of this syndrome. according to DSM-IV-TR. Excessive anxiety and worry (apprehensive expectation). GAD is the main diagnostic category for prominent and chronic anxiety in the absence of panic disorder. or having a serious illness (as in hypochondriasis). In an important finding for the application of optimal treatment in nonpsychiatric primary care settings. The largest study comparing medication. imipramine plus CBT. imipramine produced a higher quality of response than CBT alone. and anticipating the worst. 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. at 6-month follow-up after termination of treatment. Finally. gaining weight (as in anorexia nervosa). In the initial 3-month acutetreatment phase. . B. found that combined treatment was superior to antidepressant pharmacotherapy and to psychotherapy alone.. fearful. with limited advantage for combined treatment. For responders treated in the 6-month maintenance phase.g. difficult to control.. 2005). The anxiety. (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. and combination treatment acutely and longer term (Barlow et al.. and physical symptoms. and CBT plus placebo. Note: Only one item is required in children. The disturbance is not due to the direct physiological effects of a substance (e.resulted in statistically and clinically significant improvement in panic disorder after 3 months relative to medication treatment alone (Craske et al. being away from home or close relatives (as in separation anxiety disorder). DSM-IV-TR diagnostic criteria for generalized anxiety disorder A. pervasive. or a pervasive developmental disorder. 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. 2005). occupational. CBT had more durable results. Patients with GAD are constantly worried over minor matters. C. being contaminated (as in obsessive-compulsive disorder). each having its advantages and disadvantages. 2006). a medication) or a general medical condition (e. a drug of abuse. having multiple physical complaints (as in somatization disorder).g. being embarrassed in public (as in social phobia). or other important areas of functioning. Muscle tension. However. e. The symptoms of this type of anxiety fall within two broad categories: apprehensive expectation and worry. A recent meta-analytic study. based on 23 randomized comparisons involving about 1. or restless unsatisfying sleep) D.g. combination therapy was more effective than pharmacotherapy alone but as effective as psychotherapy. or physical symptoms cause clinically significant distress or impairment in social. placebo alone. 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. The focus of the anxiety and worry is not confined to features of an Axis I disorder. F. the anxiety or worry is not about having a panic attack (as in panic disorder). after termination of acute-phase treatment. a psychotic disorder. CBT alone. and associated with marked distress or impairment. medication and CBT had similar efficacy. 2000) was a multisite controlled study of 312 patients with panic disorder randomly assigned to five different treatments: imipramine alone.700 participants. E. and there was an even more substantial advantage for combined treatment. CBT. is persistent anxiety lasting at least 6 months. suggesting a more lasting effect of psychotherapy (Furukawa et al.

7%) and the elderly (2. 2005). widowed/separated/divorced. Finally. impairment.1%. with rates higher in female. Higher rates of the disorder were found in women (2. questioning the validity of the excessiveness requirement and highlighting the need for more research (Ruscio et al. 2001) found a 1. a more chronic course.2%). impairment. Although dependent and avoidant personality disorders are commonly found to co-occur with GAD. finding that the lifetime prevalence of GAD increases by about 40% when the excessiveness requirement is removed (Ruscio et al. which cannot be accounted for by comorbidity or sociodemographic variables (Kessler et al. comorbidity. and sociodemographic correlates. With regard to Axis II comorbidity. Etiology Biological Theories Although the neurobiology of GAD is among the least investigated in the anxiety disorders. Finally. The diagnosis of GAD is made when a patient experiences at least 6 months of chronic anxiety and excessive worry. a "keyed up" feeling. Those who do have excessive worry have GAD onset earlier in life. 2000). and low-income individuals (Grant et al. course. The NESARC revealed a 1-year and lifetime DSM-IV GAD prevalence of 2. middle-aged. respectively. 2005b). insomnia. 2005). difficulty concentrating. Motor tension and hypervigilance better differentiate GAD from other anxiety states than autonomic hyperactivity. and treatment seeking and share familial aggregation with those who do have excessive worry. However. the 6-month duration criterion may be arbitrary and has come under scrutiny. parental GAD. 1999a). TABLE 12–11. it is not clear whether such personality disorders are primary or consequent to the GAD itself. 2005b). impairment. mood. individuals with pure GAD actually fare worse than those with pure major depression (Wittchen et al. advances are now being made (a summary is presented in Table 12–11). thus the basis for excluding these individuals from the GAD diagnosis may need to be reexamined (Kessler et al. 2005b). even those without excessive worry manifest substantial persistence. and personality disorders (Grant et al.5% 1-year prevalence for threshold GAD and a 3. The necessity of the "excessive worry" criterion in making the GAD diagnosis has been questioned and investigated in epidemiological samples. this chronic anxiety must not be secondary to another Axis I disorder or a specific organic factor. and greater symptom severity and comorbidity. 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. and they are similar to the DSM-IV-TR-defined group in onset. On certain quality-of-life indexes. 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. A high degree of comorbidity was again confirmed: 59% for major depression and 56% for other anxiety disorders. Epidemiology and Comorbidity One epidemiological study using DSM-IV criteria (Carter et al. At least three of six physical symptoms must also be present. irritability. GAD and depression each show their own statistically significant and independent associations with impairment. 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 .1% and 4. the personality types of patients with GAD have not been well characterized. 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).restlessness. and prognosis. comorbidity. 2005). Despite its high comorbidity with substance use and other anxiety. GAD stands on its own as a disorder with distinct onset. persistence. Similarly. The National Comorbidity Survey database has shown that a large number of people have a GAD-like syndrome of 1–5 months' duration. of roughly equal magnitude.6% 1-year prevalence for subthreshold GAD.

individuals with GAD engage in a certain degree of magical thinking and believe that their worry helped prevent a feared outcome. Finally. anxious early attachments to important caregivers (Cassidy 1995). Rocca et al. People with GAD do not show heightened sensitivity to 35% CO 2 inhalation as do people with panic. 1981). such as heightened anxiety responses to the partial serotonin agonist meta-chlorophenylpiperazine (m-CPP) compared with control subjects (Germine et al. and 2 adrenoreceptors decreased. Other studies of the noradrenergic system have been negative (R. 1999). Children with GAD were found to have larger right and total amygdala volumes (DeBellis et al. 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. supporting the conceptualization of GAD and panic as two discrete disorders (Perna et al. Mathew et al. Regarding mechanisms that may perpetuate GAD. 1990. benzodiazepines are well established as an efficacious treatment of GAD. With regard to its origins. Kendler et al. with increased neuronal firing in the serotonergic dorsal raphe (Senkowski et al. in GAD patients compared with normal control subjects (Sevy et al. that have suggested associations to polymorphisms of the dopamine D2 receptor gene. Accordingly. whereas panic disorder patients have more cognitions related to physical catastrophes (Breitholtz et al. cognitive theory speculates a relationship to early cognitive schemas born from negative experiences of the world as a dangerous place (Barlow 1988) or insecure. three are summarized. produce an acute anxiety syndrome when administered to laboratory animals or to normal human volunteers. Abnormalities of the GABA–benzodiazepine receptor complex have also been implicated in GAD. worrying about the worrying in . thus leading to a negative reinforcement of the process of worrying. Evidence for noradrenergic dysregulation in GAD has yielded mixed results. Psychological Theories Cognitive hypotheses regarding both the origins and maintenance of GAD have been thoroughly summarized in recent work (Aikins and Craske 2001). Similarly. 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. 1989). whereas environmental influences on GAD and neuroticism were largely unshared (Hettema et al. effectively slowing neural transmission. 1997b). may all contribute to later development of anxiety. Auditory evoked potentials have revealed disturbed exteroceptive sensory processing in GAD at the level of the primary auditory cortex. The prefrontal cortex and medial temporal lobe are involved in controlling fear and anxiety. 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. may be associated with GAD. requiring replication. J. There is also evidence that the process of meta-worry—that is. worry is used as a strategy for avoiding intense negative affects. possibly accounting for the observed arousal and hypervigilance (Buchsbaum et al. It is speculated that alterations in the structure and function of the amygdala. albeit relatively modest. 1987. acceptance. the -carbolines. 2004). which are inverse agonists of this receptor complex. it has been proposed that insecure attachment relationships and ambivalence toward caregivers. Second.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. There appears to be a genetic component to GAD. (1992) studied GAD in female twins and determined that the familial component of the disorder was almost entirely genetic. First. 1998). 2003). and worry over minor matters. the dopamine transporter gene. Abelson et al. competence. 1999). Wu et al. the serotonin transporter gene. which are central to fear-related behaviors. 1991). Plasma norepinephrine and its metabolite were found to be elevated. Twin studies have reported about 20%–33% overlap in genetic influences between GAD and neuroticism. (1991) reported a blunted growth hormone response to clonidine in GAD compared with responses in normal control subjects. 1992). In terms of the etiology of GAD. with a modest heritability of about 30%. and the monoamine oxidase-A gene. both of which return to normal values with treatment and reduction in anxiety levels (Ferrarese et al. One series of compounds. Binding of a benzodiazepine to the benzodiazepine receptor facilitates the action of GABA. as well as parental overprotection and lack of emotional warmth. There have been minimal molecular genetic studies of GAD to date. and there is evidence for heightened cortical activity and decreased basal ganglia activity in GAD. The benzodiazepine receptor is linked to a receptor for the inhibitory neurotransmitter GABA. concern about others. There is some evidence for specificity in cognitive content in the various anxiety disorders. GAD patients demonstrate more cognitions in the categories of interpersonal confrontation. There is also some evidence of serotonergic dysregulation in GAD. 2000). 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.

and anxiety is excessive. certain information-processing biases may characterize GAD and permit the perpetuation of worry as the central cognitive strategy (Aikins and Craske 2001). and overall greater difficulty managing emotional reactions (Mennin et al. These include a bias for threat-related information in implicit memory processes (MacLeod and McLaughlin 1995). diminished ability to self-soothe after negative emotions. Comorbid avoidant and dependent personality disorders appear to lessen the likelihood of remission from GAD (Massion et al. and a tendency to view GAD as a secondary or minor condition hampered past treatment research. 1993). 1989. In addition. GAD is a more chronic condition than panic disorder. Such patients seem only over time to develop the recognition that their experience of chronic tension. poorer understanding of emotions. disturbed family environments. the distinction between GAD and "normal" anxiety must be made. Yonkers et al. dementia. and greater social maladjustment (Hoehn-Saric et al. 2000). course. In clinical samples. TABLE 12–12. have more severe anxiety that may not be precipitated by specific stressful events. Abuse of alcohol. Of GAD subjects followed over a 5-year period. An emotional dysregulation model has also been proposed for GAD. pharmacotherapy options have blossomed in recent years. in GAD the worry must be clearly excessive. based on evidence from both nonclinical and clinical samples reporting heightened intensity of emotions. hyperactivity. difficult to control. and have histories of more childhood fears. 2005). only 18%–35% achieved full remission (Woodman et al. and depression or could be manifestations of underlying medical illnesses. and associated with marked distress or impairment. pervasive. Finally. often occurring comorbidly with medical illnesses (Flint 1994). with fewer periods of spontaneous remission. We now know that clinicians must be cautious and conservative in applying this criterion. GAD is commonly comorbid with major depression and other anxiety disorders but still emerges as a clearly distinct entity (Wittchen et al. 2002). the presence of frequent comorbidity. GAD patients with an earlier onset of anxiety symptoms in the first two decades of life appear to be overall more impaired. and difficulty in decision making when faced with ambiguity (MacLeod and Cohen 1993). Course and Prognosis In contrast with panic disorder. GAD appears to account for a lot of the anxiety states in late life.itself—contributes to the high degree of pathological worry in GAD (Wells and Carter 1999). 1994). worry. Although the major changes in diagnostic criteria in consecutive editions of DSM. selective attentional biases for threatening information (Mogg et al. barbiturates. 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. 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. greater negative reactivity to emotional experiences. which declines with old age. and associated impairment. as long as they can remember. GAD is clearly a discrete disorder in terms of its onset. psychosis. and antianxiety medications is also common. Contrary to panic disorder. . that they were not anxious. because as previously described. Often they will state that there has never been a time in their lives. In these elderly patients it is particularly important to differentiate GAD from other anxiety states that could be related to delirium. Differential Diagnosis The diagnosis of GAD is excluded when occurring exclusively in relation to other major Axis I disorders. 1996). 2000). 1999. no overwhelming single event prompts the patient with GAD to seek help. there are now compelling data demonstrating that even in the presence of high comorbidity of GAD with other anxiety and mood disorders. The differential diagnosis of GAD is summarized in Table 12–12.

there is a concern that some patients may become tolerant or even addicted to these medications. Pharmacological treatment of generalized anxiety disorder Venlafaxine extended-release General indications: First-line treatment. mixed results Pregabalin: not marketed in United States Note. Its advantages are a different side-effect profile without sedation and the absence of tolerance and withdrawal. paroxetine is FDA-approved. maintenance. benzodiazepines were the first-line treatment of GAD. compared with benzodiazepines. and discontinuation of patients with GAD. SSRIs. Concerns over addiction are probably justified. which may be adequate for many patients. Buspirone Buspirone is a 5-HT1A agonist. may be more effective in treating the psychic symptoms (Rocca et al. A number of controlled studies clearly show that chronically anxious patients respond well to benzodiazepines. 1995). 1998). in individuals with histories of addiction proneness. whereas antidepressants. with side effects limited mainly to sedation and slowed mentation. buspirone. recommended starting dosage is 75 mg/day. delayed action compared with benzodiazepines. Its disadvantage is a slower rate of onset (Rickels et al. well tolerated. a trial is generally indicated in all patients. approved by FDA. and all benzodiazepines are probably similarly efficacious in treating GAD. newer medication choices such as buspirone. There is some evidence that benzodiazepines may be more effective in treating the physical symptoms of anxiety. generally well tolerated. all appear similarly efficacious. FDA = U. (1988) compared the efficacy of the benzodiazepine clorazepate to the nonbenzodiazepine buspirone in the acute treatment. and serotonin and norepinephrine reuptake inhibitors (SNRIs) have replaced the benzodiazepines as first-line treatments.S. Although benzodiazepines are generally safe. takes longer to take action and is not associated with a "high". once-daily dosing. more side effects than benzodiazepines. and in reality most patients continue to derive clinical benefits without developing abuse or dependence (Romach et al. Selective serotonin reuptake inhibitors (SSRIs) General indications: First-line treatment. other SSRIs also efficacious. 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. Benzodiazepines In past years. The two . available data indicate that the concern over benzodiazepine abuse in chronically anxious populations is overestimated. 1988). Rickels et al. recommended starting dosage is 20 mg/day. may be more effective for cognitive rather than physical symptoms of anxiety. Currently. whether TCAs or SSRIs. However. may be more effective for the physical rather than cognitive symptoms of generalized anxiety disorder. Food and Drug Administration.TABLE 12–13. once-daily dosing. which can lead to early patient noncompliance. however. and newer antidepressants. Benzodiazepines General indications: Well-known efficacy and widely used. issues with dependence and withdrawal in certain patients. generally well tolerated. Buspirone General indications: Proven efficacy. for the most part. Tricyclic antidepressants (TCAs) General indications: Demonstrated efficacy in few trials. may have less efficacy and compliance with very recent benzodiazepine use. which may be adequate for a number of patients. with proven efficacy in large controlled trials. nonbenzodiazepine antianxiety agent that may have similar efficacy to the benzodiazepines in treating GAD.

both medications were superior to placebo. and diazepam up to 26 mg/day were found comparable after 8 weeks of treatment. 1995). Venlafaxine has been found effective in dosages ranging from 75 to 225 mg/day. In a trial comparing venlafaxine 75–150 mg. that in long-term benzodiazepine users. Antidepressants Over the past few years. measures (Davidson et al. an SNRI. 2000). with benefits appearing as early as the first 2 weeks of treatment. Gelenberg et al. There was no evidence of tolerance to either medication over the 6-month period. 2000. because controlled trials have documented their efficacy and because they tend to be well tolerated. The SSRI paroxetine has been studied in several controlled trials. In addition. trazodone up to 255 mg/day. 2004). or 50 mg daily (McCafferty et al. 2005) at flexible dosages of 50–150 mg/day (Allgulander et al. 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. Several large controlled trials to date have established the efficacy of extended-release venlafaxine. newer antidepressants have become established as first-line treatments for GAD. somnolence. 2003). 2000). 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. 1999. administered for 8 weeks at a dosage of 10–20 mg/day. They found that clinical response to buspirone was similar to benzodiazepine response in patients who had never used or had remotely used benzodiazepines. 40. and the dosage can be increased until a maximum dosage of 60 mg/day is reached. Treatment with buspirone is usually started at 5 mg tid. 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. but not all. reported significant improvement in GAD with good tolerability in more than 800 patients (Goodman et al. and one study showed comparable efficacy and tolerability for paroxetine and sertraline (Ball et al. 2005). 2000). require only once-daily dosing. On the other hand. (2000) retrospectively analyzed a large data set with respect to history of benzodiazepine use prior to a controlled clinical trial. Other independent predictors of successful benzodiazepine taper were lower initial dosages and less severe and chronic anxiety symptoms. 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. In one controlled study comparing imipramine and alprazolam in treating GAD. similar efficacy was found for the two medications. In another study. buspirone 30 mg. There is recent evidence. Several older studies have shown TCAs to be effective in treating chronically anxious patients independent of the presence of depressive symptoms. imipramine up to 143 mg/day. a controlled treatment study has refuted this. However. Rickels et al. 2001). and benefits were maintained over a 6-month period. with approximately two-thirds of patients considered responders (Bellew et al. and do not risk abuse and dependence. via a controlled trial (Rickels et al. Response rate is approximately 70%. 1999). with about . 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. Studies have not revealed consistent differences in efficacy as a function of dosing. In the first 2 weeks of medication discontinuation. Three pooled similar placebocontrolled trials of the SSRI escitalopram.medications had similar efficacy by the fourth week of treatment. SSRIs are also efficacious in treating GAD. 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. patients who had been on clorazepate had a transient increase of anxiety consistent with withdrawal. an approximately 65% response rate and 33% remission rate were reported (Rickels et al. There has existed a suggestion in the literature that patients previously treated with benzodiazepines may not respond successfully to buspirone. 2003). and placebo in GAD without depression over an 8-week period. in treating GAD (Davidson et al. with nausea. whereas those who received buspirone did not. with imipramine acting more on negative affects and cognitions and alprazolam acting more on somatic symptoms (Hoehn-Saric et al. A twice-daily regimen is probably as efficacious as a thrice-daily regimen and easier to comply with. In a paroxetine trial using dosages of 20–40 mg/day. 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. with an approximately 60% reduction of anxiety scores. DeMartinis et al. 2001). 2005). and dry mouth being the most common side effects. 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. Venlafaxine is generally well tolerated. 1988). 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. although TCA use has largely fallen out of favor recently in favor of the newer antidepressants. and there was weak evidence for possible superiority of venlafaxine over buspirone by some.

but the medication was well tolerated overall (Pohl et al. 2005). 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). Riluzole. In contrast. behavioral anxiety management. the effect of risperidone augmentation in patients not adequately responding to standard anxiolytic treatment was found to be marginal (Brawman-Mintzer et al. has been tested in a double-blind design (Pollack et al. with efficacy demonstrated by some analyses but not by the primary intent-to-treat analysis (Pollack et al. Similarly. an antiglutamatergic agent. have reported efficacy at dosages ranging from 150 to 600 mg/day. A recent open trial reported that mirtazapine. the combined CBT group had a much lower dropout rate than the other groups (Barlow et al. A multicenter placebo-controlled study of the selective GABA reuptake inhibitor tiagabine. 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. 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. analytic. makes clonidine a poor initial choice for treatment. 2005. a calcium-binding presynaptic inhibitor of excitatory neurotransmission. including cognitive restructuring. 1994). reported mixed results. plus a number of bothersome side effects.7 mg/day. These include the heightened tendency to perceive threat. Psychotherapy Research into the psychotherapy of GAD has not been as extensive as for other anxiety disorders. exposure therapy with or without a cognitive component. Cognitive therapy emerged as superior. Clonidine. has also been studied in an open-label trial and appears promising. Rickels et al. 2005). SSRI augmentation with the atypical antipsychotic olanzapine. 1991). poor problem solving. 2005). fairly rapid onset. administered for 8 weeks at dosages of 4–16 mg/day. Cognitive therapy alone may have an edge over behavioral therapy alone according to some studies (Butler et al. 1992). at a mean dosage of 8. with some edge over behavioral management alone and a significantly better result than analytic treatment. the expectation of low-likelihood catastrophic outcomes. generally demonstrating superiority to placebo. the central feature of worry. resulted in at least 50% improvement in 80% of 44 patients (Gambi et al. dizziness and sedation are reported at higher dosages. which inhibits locus coeruleus discharge. and the physical symptoms of anxiety. a number of studies exist that clearly show that a variety of psychotherapies are helpful in treating GAD (Table 12–14). Placebo-controlled trials of the new anxiolytic pregabalin. Still. A tendency to lose clinical response. an open monotherapy trial of ziprasidone in 13 patients with treatment-resistant illness reported more positive findings. however. and psychodynamic treatment. J. 2005). 84% of patients responded and 46% remitted after 7 weeks of treatment with ziprasidone. such as relaxation and rebreathing techniques. Other Medications -Adrenergic-blocking drugs such as propranolol may only be rarely indicated as an adjuvant in patients who experience significant palpitations or tremor. 2005). In patients with refractory GAD. A variety of treatments have been developed for GAD. In a study that compared four conditions—behavioral therapy alone. TABLE 12–14. but not others (Ost and Breitholtz 2000). 2005). cognitive therapy alone. several aspects of the disorder can serve as the foci of psychotherapeutic interventions. especially in the face of ambivalence or ambiguity. 2005). Mathew 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). 20–80 mg/day (Snyderman et al. A "well-being" component aimed at restoring overall function may be a useful addition to usual CBT (Fava et al.two-thirds of GAD patients experiencing moderate to marked improvement in anxiety. and behavioral management in treating subjects with GAD (Durham et al. at a daily dosage of 30 mg for 12 weeks. 2005) and showed modest benefit for some patients. combined CBT. and similar response to a benzodiazepine active control group. would seem for theoretical reasons to be a good antianxiety drug. Combined Pharmacotherapy and Psychotherapy . with 12 of 15 completers responding to the 8-week treatment (S. Another randomized study compared cognitive.

DSM-IV-TR diagnostic criteria for social phobia A. e. which may take the form of a situationally bound or situationally predisposed panic attack. it has an earlier onset. or social activities or relationships. Exposure to the feared social situation almost invariably provokes anxiety. CBT alone or with medication tended to emerge as superior. freezing. this feature may be absent. body dysmorphic disorder. F. The individual fears that he or she will act in a way (or show anxiety symptoms) that will be humiliating or embarrassing. Interestingly. a common fear of socially phobic individuals is that other people will detect and ridicule their anxiety in social situations. There are minimal data on the use of combined psychotherapy and medication in the treatment of GAD. a medication) or a general medical condition and is not better accounted for by another mental disorder (e. the duration is at least 6 months. Blushing is the cardinal physical symptom characteristic of social phobia. or exhibiting abnormal eating behavior in anorexia nervosa or bulimia nervosa. and placebo (Power et al. or writing in public. It appears. tantrums. there must be evidence of the capacity for age-appropriate social relationships with familiar people and the anxiety must occur in peer settings. Actual panic attacks may also occur in individuals with social phobia in response to feared social situations. and dry mouth are more common in social anxiety. overall similar efficacy was reported for the two treatment approaches. C. the anxiety in social phobia is stimulus bound. whereas commonly encountered cognitive constellations include tendencies for self-focused attention. blushing. palpitations and chest pain or pressure are more common in panic attacks. and attending parties or interviews. persistent fear of social situations in which public humiliation or embarrassment is possible. G. and further studies are clearly needed in this area. An individual may have one. 1995). with lower attrition rates for psychotherapy (Mitte 2005). 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. DSM-IV-TR criteria for social phobia are presented in Table 12–15.. the fear is not of stuttering. using public lavatories. TABLE 12–15. In addition.. the fear in criterion A is unrelated to it. or shrinking from social situations with unfamiliar people. The fear or avoidance is not due to the direct physiological effects of a substance (e. H. negative self-evaluation regarding social performance. or schizoid personality disorder). D. occupational (academic) functioning. Typical social phobias are of speaking. Generalized social phobia can be reliably diagnosed as a subtype. Note: In children. E. In individuals under age 18 years. and affected individuals are more often single and have more interactional fears and greater comorbidity with atypical depression and alcoholism (Mannuzza et al. different anxiety disorders tend to be characterized by their own constellation of most prominent somatic symptoms. If a general medical condition or another mental disorder is present. a combination of the two. difficulty gauging nonverbal aspects of one's behavior. or there is marked distress about having the phobia. however. trembling in Parkinson's disease. limited. The person recognizes that the fear is excessive or unreasonable.g. that the CBT component of the study was more intensive than the medication treatment. the anxiety may be expressed by crying. or distress in the feared social or performance situation(s) interferes significantly with the person's normal routine. the individual experiences profound anxiety accompanied by a variety of somatic symptoms. panic disorder with or without agoraphobia.g. discounting of social competence . B. In one study comparing CBT. Note: In children. When forced or surprised into the phobic situation. eating.g. a pervasive developmental 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. Social phobia is described as generalized if the social fear encompasses most social situations as opposed to being present in circumscribed ones. not just in interactions with adults. 1990). separation anxiety disorder. a drug of abuse. whereas sweating. The feared social or performance situations are avoided or else are endured with intense anxiety or distress.. SOCIAL PHOBIA (SOCIAL ANXIETY DISORDER) Definition and Clinical Description The central feature of social phobia is a marked. The avoidance.In a meta-analysis of 65 CBT and pharmacological treatment studies of GAD. anxious anticipation. Note: In children. For example. Generalized social phobia is overall a more serious and impairing condition. or numerous social fears. benzodiazepine. As in specific phobias.

especially GAD. Socially phobic persons are impaired on a broad spectrum of measures. social phobia had a lifetime occurrence of 13. fears of negative social evaluation. Indeed. 2005). Multiple social fears. Hispanic. particularly avoidant personality disorder. pervasive and serious functional impairment can already be found. 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. mean age at first treatment was about 12 years later. When faced with this necessity. 15. In epidemiologically identified probands with social phobia alone.5% and was somewhat more common in women than in men (lifetime. Risk factors for social anxiety Parental psychiatric history (especially social phobia. Even in preadolescent children. can lead to chronic demoralization. suggesting that the Axis I and II disorders may represent dimensions of social anxiety rather than discrete conditions (Tillfors et positive interactions. 2001a). they are often subject to intense anticipatory anxiety. depression. which was found to be more persistent. about one-third reported exclusively public speaking fears. other anxiety disorders. Social phobia. Being Native American. and risk factors for social anxiety are summarized in Table 12–16. The NESARC found a 1-year and lifetime prevalence of DSM-IV social anxiety disorder of 2. social isolation. 11. and the quality of their life is rated as quite low. depression. possibly leading to abuse. Etiology Psychosocial Theories A number of mechanisms are proposed in learning theories as contributors to the pathogenesis of social phobia (Stemberger et al.3%. impairing. and bipolar disorder (Kessler et al. avoidant personality disorder alone. ranging from dropping out of school to experiencing significant disability in whatever their main activities are. Alcohol and sedative drugs are often utilized to alleviate at least the anticipatory component of this anxiety disorder. 2005a). the latter were found to be younger. being young in age. 1994. 1995). whereas the rest were characterized by at least one other social fear.5% vs. and a positive bias toward appraising others' social performance (Alden and Wallace 1995). 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. and unemployment (Heimberg et al. They describe dissatisfaction with many aspects of life. 1999b).to sixfold higher risk for dysthymia. 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. In a study that systematically compared individuals with a public speaking phobia with those with generalized social phobia. and comorbid than the specific public speaking type. with an approximately three. and 80% had never received treatment. Social phobia can be associated with a variety of personality disorders. About one-third had multiple fears qualifying for the generalized type of social phobia. and disabling vocational and interpersonal impairment. depression) Parental marital conflict Parental overprotection or rejection Childhood abuse . per se. whereas being male. comorbid depression seems to contribute only modestly to these outcomes. bipolar I. being Asian. and 1-month incidence of 4. or African American. which employed DSM-III-R criteria. 1996).8% and 5. Importantly. or both. Epidemiological studies have consistently found significant comorbidity between lifetime social phobia and various mood disorders. 1-year incidence of 7. avoidant personality disorder.9%. Epidemiology and Comorbidity In the National Comorbidity Survey (Kessler et al. Of those affected.0%. and avoidant and dependent personality disorders. a review of the literature comparing generalized social phobia. TABLE 12–16. is a highly disabling disorder whose impact on functioning and quality of life has probably been greatly underestimated and hidden in past years. There was significant comorbidity with other psychiatric disorders. The disorder was chronic. or having low income increased risk. Magee et al. 1990b).1%). or living in urban settings reduced risk. a similarly elevated familial risk of social phobia has been found. respectively (Grant et al. and have greater anxiety. less educated. on the other hand. Mean age at onset was 15 years.

moving several times as a child. and fewer positive outcomes from peers (Spence et al. running away from home. more negative self-talk. There is a significant familial component to social phobia. all centering around various manifestations of a core negative representation of one's social self. any alcohol use disorder. and fearful information conveyed about social situations (Hudson and Rapee 2000). modeling of socially anxious behaviors. childhood abuse. 2005a). Other potential risk factors for social phobia identified in a large epidemiological sample include lack of a close relationship with an adult. have difficulty disengaging attention from threatening material (Amir et al. TABLE 12–17. might rear socially anxious children through various mechanisms. Types of family adversity also appear to affect females differently than males (DeWit et al. while in females the disorder was associated with parental conflict and paternal physical abuse during childhood. compared with their nonanxious peers. have an attentional and implicit memory bias for socially threatening information (Rinck and Becker 2005). part of which is thought to be heritable (see section "Genetics" later in this chapter) and part acquired. parental marital conflict. Parental social phobia is a strong risk factor for social phobia among adolescent offspring. 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 . and parental overprotection or rejection. less competent social performance with peers. have faulty learning of nonthreatening meanings (Amir et al. any other anxiety disorder. A number of cognitive distortions have been identified in individuals with social phobia. For example. things that one hears in various contexts regarding social interactions). and information transfer (i. have persistent postevent negative self-appraisal ruminations (Abbott and Rapee 2004). 1996). general parental psychiatric history. Children with social phobia. whether socially anxious themselves or not. 2001). make negative interpretations of ambiguous social events and catastrophic interpretations of mildly negative social events (Stopa and Clark 2000).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. not being firstborn for males. such as lack of adequate exposure to social situations and development of social skills. 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. have been found to have social skills deficits. 2001). have a diminished perception of control over anxiety-related symptoms (Hofmann 2005). 2000). 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. Parents. controlling and critical behavior. 2003). are flexible in interpreting anxiety symptoms exhibited by others but are more judgmental of their own (Roth et al. 2005).e. 1999).. and have a negative expectation that social success will result in greater future social demands (Wallace and Alden 1997). overprotectiveness. vicarious learning through observing others engaged in such traumatic situations. overall family functioning was not predictive (Lieb et al. Biological Theories Biological theories of social phobia are summarized in Table 12–17. and doing poorly in school (Chartier et al. 2001). as is parental depression.

2004). 2002). whereas phobic subjects . all areas involved in emotional processing. B. Stein et al. each disorder for its specific triggers. suggesting underlying noradrenergic dysfunction (Tancer et al. Magnetic resonance spectroscopy has shown significantly higher glutamate levels in the anterior cingulate of patients with social anxiety compared with control subjects. fMRI imaging has shown greater activity in the subcortical. in response to emotionally neutral faces during fMRI (Birbaumer et al. One study found increased cortisol response to fenfluramine suggestive of altered serotonergic sensitivity (Tancer et al. Several imaging studies have demonstrated heightened brain activation in social phobia in brain regions associated with emotional processing. socially phobic patients showed greater anterior cingulate activation than nonanxious control subjects when processing disgust versus neutral faces (Amir et al. Stein et al. Social phobia was associated with a significant 20% decrease in dopamine transporter site density in the striatum on SPECT (Tiihonen et al. 1998). 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. Two studies have found normal basal functioning of the HPA axis in social phobia. 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. which correlated with the severity of social anxiety symptoms (Phan et al. Despite the now-documented efficacy of serotonin reuptake inhibitors in treating social phobia. 2000). fearful. GABA–benzodiazepine receptor involvement is unclear. Patients with social phobia exhibit a blunted growth hormone response to clonidine challenge. B. compared with happy faces (M. 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. whereas the amygdalae were relatively deactivated (Bell et al. the dorsolateral prefrontal cortex. 1994). In a PET study utilizing social anxiety–provoking scripts. 1994). 1997a) and with decreased dopamine D2 receptor binding potential (Schneier et al. In another fMRI study. However. More recently. which correlates with symptom severity (Phan et al. 1998). A PET imaging study reported that during a public speaking task. 2006b). 1994). Uhde et al. similar to that described for panic disorder and involving faulty conditioned fear responses. 1999). Neuroimaging Provocation paradigms that evoke social anxiety have blossomed over the past several years and have consistently highlighted dysfunctional brain circuits in social phobia. again suggesting diminished cortical inhibition of automatic emotional processing (Lorberbaum et al. the orbitofrontal cortex. However. 1999). a center for the emotional processing of fearfulness. PET imaging has shown significant deactivation in the lingual gyrus and medial frontal gyrus in socially phobic patients during exposure to public speaking. 2005).disorder. A model involving the neurocircuitry of fear. suggesting a strategy of visual avoidance employed to dampen phobic anxiety (Van Ameringen et al. An fMRI study found heightened amygdala activation in socially phobic persons compared with control subjects when viewing angry or disgusted faces. 2004b). including the noradrenergic. Along these lines. 1998). and the insula. including socially threatening cues in social phobia. has also been implicated in other anxiety disorders. whereas socially phobic subjects exhibited opposite increased activations in both regions (Schneider et al. 2004). However. GABAergic. socially phobic participants showed greater amygdalar activation than control subjects in response to the harsh faces. 2002). 1994). 1995a) and no abnormality in the prolactin response to m-CPP (Hollander et al. as measured by basal cortisol levels and the dexamethasone suppression test (Condren et al. dopaminergic. 1993). Johnson et al. and serotonergic systems. individuals with social phobia showed greater blood flow in the anterior cingulate. nonphobic subjects revealed relatively increased cortical rather than subcortical activity. another study showed significantly decreased peripheral benzodiazepine receptor density in subjects with generalized social phobia compared with a healthy group (M. suggesting that improvement in social anxiety by SSRIs is mediated via increased serotonin availability (Argyropoulos et al. disgusted) faces. little is directly known about serotonergic involvement in the disorder. limbic. a tryptophan depletion protocol resulted in significant increase in anxiety during an autobiographical script in SSRI-treated social anxiety patients. R. 2005b). but they have to date implicated a number of neurotransmitter systems. In an fMRI study examining amygdalar activation to happy versus harsh (angry. 2000). other studies found no evidence of altered serotonin reuptake sites in platelets in social phobia (M. A study comparing socially phobic individuals with healthy control subjects demonstrated selectively higher activation in the amygdala. but this was not replicated in a subsequent study (Tancer et al. 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. 2002. There is also evidence that social phobia may be associated with a decreased central dopaminergic tone. Johnson et al. under psychosocial stress socially phobic individuals did manifest a significantly more robust peak cortisol response compared with control subjects (Condren et al.

and absence of comorbid health problems or depression or the occurrence of comorbid illness prior to the onset of social phobia (DeWit et al. has revealed findings along the same lines. First-degree relatives of probands with generalized social phobia have an approximately 10-fold higher risk for generalized social phobia or avoidant personality disorder. absence of psychiatric comorbidity. One report found no linkage to the serotonin transporter or 5-HT2A receptor gene in generalized social phobia (M. It has been found that more than half of social phobia patients report significant impairment in some areas of their lives. 2004). 2004). Course and Prognosis Social phobia has its onset mainly in adolescence and early adulthood. in the form of both social avoidance and fearfulness in early high school. One twin study has not supported a genetic component to social and specific phobia. onset after age 7 years. Genetics A strong familial risk for social phobia has been identified that is believed to be partly heritable and partly environmental. and neighboring cortical areas. in distinction to other anxiety disorders. The short allele of the serotonin transporter gene has been implicated in vulnerability to mood disorders (Hariri et al. which is believed to be largely heritable and becomes manifest and fixed in early childhood (Kagan et al. 2000). earlier than with agoraphobia. with a median illness duration of 25 years. 1999). 2000). however. prospectively predicted the onset of social phobia 4 years later in adolescence (Hayward et al. suggesting environmental causation (Skre et al. but it is neither necessary nor sufficient for the development of the disorder. with strong evidence for shared genetic vulnerability between social phobia and major depression (Nelson et al. 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. independent of the degree of social support (Stein and Kean 2000). rather than prevalence rates in the population at large. Gelernter et al. 2002). men are equally or even more commonly affected than women. coupled with treatment interventions. Yet another study has confirmed better prognosis with medication treatment for later disorder onset (especially adult onset) compared with . In a large retrospective survey of individuals ages 15–64 years with lifetime social phobia. and the course of illness is very chronic. GAD. A genomewide linkage scan study reported strongest linkage to chromosome 16 in a region implicating the norepinephrine transporter gene (J. Significant predictors of recovery were childhood social context. 1999). This may reflect who is more likely to seek treatment under societal role demands. 2005). 1993). Interestingly. fewer symptoms. Schwartz et al. Mean age at onset is around 19 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. The short allele of the serotonin transporter gene (5-HTT) has been implicated in vulnerability to mood disorders (Hariri et al. There are few genetic molecular studies in social phobia. 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. B. in clinical studies. approximately half of the sample had recovered from their illness at the time of survey. Social phobia is clearly a chronic and potentially highly impairing condition. and higher educational status (Davidson et al. and hippocampal-parahippocampal regions (Furmark et al. Comorbid avoidant personality disorder has been found to predict a 41% lower likelihood of social phobia remission (Massion et al. behavioral inhibition. and PTSD. course and prognosis are summarized in Table 12–18. amygdala. An adolescent female twin study has estimated the heritability of social phobia to be 28%. 1998). 1993b). hippocampus. 1998a). 1987). A PET study examining brain activation in response to a public speaking task found that after treatment with citalopram or CBT. 2004). Predictors of good outcome in social phobia are onset after age 11 years. to be a strong predictor of social anxiety in adolescence (C. Similarly. prospectively. and there is evidence that it may also be implicated in anxiety disorders such as social anxiety disorder (Furmark et al. suggesting common sites of action of the two treatments (Furmark et al. 2001b). Neuroimaging. brain activity was attenuated in the amygdala. in contrast to panic disorder. Behavioral inhibition assessed in toddlerhood has been found. 2005). 2002). The personality trait of behavioral inhibition. Stein et al. is thought to be one of the substrates onto which social phobia might develop.showed increased subcortical activity (Tillfors et al. such as no siblings and small-town rearing. Medication treatment resulted in decreased cerebral blow flow in responders during a public speaking task in the rhinal cortex. 2005).

social anxiety disorder in nondepressed adolescents and young adults at baseline was associated with an increased likelihood of depressive disorder during a 3. Stein et al. 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. Avoidance of social situations is seen as part of avoidant. the presence of other disorders that may cause irrational fear of people and avoidance behaviors must be ruled out. schizophrenia. 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. 2001a). The distinction between this entity and generalized social phobia may be conceptual and semantic. depressive disorders. and its validity is a subject of dispute. 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.g. Automatically labeling such patients as having avoidant personalities may lead practitioners away from potentially useful pharmacotherapy and behavioral treatment efforts. 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. TABLE 12–18. In avoidant personality disorder the central fear is also rejection. In contrast. B. schizoid. agoraphobia. 2004c). schizoid. Interpersonal anxiety or fears of humiliation leading to social avoidance are not diagnosed as social phobia when occurring in the context of schizophrenia. In contrast.earlier onset. Before the diagnosis of social anxiety disorder can be made.. individuals with social phobia generally express the wish to be able to interact appropriately with others and anticipate pleasure in this eventuality. ridicule. those with social phobia fear that they themselves will act inappropriately and cause their own embarrassment or humiliation. and major depressive disorder. schizophreniform or brief reactive psychoses. TABLE 12–19. such as avoidant. or humiliation by others. moreover. and paranoid disorders. Differential diagnosis of social anxiety disorder Personality disorder. . comorbid social anxiety in adolescents who were already depressed was associated with a more malignant course of the depressive illness (M. even when accounting for severity and duration of illness (Van Ameringen et al. more for symptom improvement but also for work impairment. Some agoraphobic patients say that they are afraid they will embarrass themselves by losing control if they panic while in a social situation. OCD. 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 ( 4-year follow-up period. 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. In a prospective epidemiological study.

than are benzodiazepines. once-daily dosing. Although a variety of -blockers have been used in studies and are probably efficacious for performance anxiety. There are a number of medication options that are clearly helpful. average dosage 40 mg/day Other SSRIs: also efficacious Venlafaxine: also efficacious Mirtazapine: also efficacious. generally well tolerated. which may decrease subjective anxiety but not optimize performance and may have an adverse effect on "sharpness. 20 mg. Phenelzine: most studied Tranylcypromine: also effective Other medications Gabapentin: effective in one controlled trial Buspirone: well tolerated. 50 mg. taken on an as-needed basis about 1 hour before event.Treatment Pharmacological Treatment The pharmacological treatment of social anxiety disorder is summarized in Table 12–20. social phobia. with minimal or no side effects. atenolol Monoamine oxidase inhibitors (MAOIs) General indications: Demonstrated high effectiveness. well worth trying in patients with otherwise refractory illness. tremor. It also seems that they are more effective in controlling stage fright..S. the most common ones used are propranolol." . panic. nonclinical samples with performance or social anxiety) studies have shown -blocker efficacy. particularly when these agents are used acutely prior to a performance. Pharmacological treatment of social anxiety disorder Selective serotonin reuptake inhibitors (SSRIs) General indications: First-line treatment. generalized anxiety disorder. FDA-approved. several analogue (i. Many performing artists or public speakers find that -blockers. or atenolol. FDA = U. or obsessive-compulsive disorder. may be difficult to tolerate and require dietary restrictions. effective for several comorbid conditions including atypical depression. reduce palpitations. taken about 45 minutes before a performance. Food and Drug Administration. taken orally a few hours before stage time. Propranolol. 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. For the most part not helpful in patients with generalized social phobia. Paroxetine: best studied in large controlled trials. fewer data Benzodiazepines General indications: Clinically widely used and reportedly efficacious in open trials.e. shown efficacy. Beta-blockers In performance-type social phobia. TABLE 12–20. well tolerated. Clonazepam: long-acting. and panic. and the "butterflies" feeling. efficacy demonstrated in controlled trial Beta-blockers General indications: Highly effective for performance anxiety. concerns about dependence and withdrawal in certain patients. effective for comorbid depression.

Liebowitz et al. and placebo in the treatment of patients with . Fluvoxamine. demonstrated significant benefit over placebo in social anxiety symptoms and social impairment. Additionally.0 mg/day (mean dosage. 1993a). using flexible dosing up to 200 mg/day and a 53% response rate (Van Ameringen et al. newer antidepressants have been tested and have shown efficacy in treating social phobia. However.4 mg/day) was found to be superior to placebo. given at 150 mg/day for 12 weeks. 1999. easy to dispense and monitor. 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%). 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. S. a 12-week large sertraline trial using dosages of 50–200 mg/day demonstrated superiority to placebo. 1993) and an open trial of citalopram (Bouwer and Stein 1998). Monoamine oxidase inhibitors MAOIs were the medications proven most effective in treating generalized social phobia until recently. Paroxetine is FDA approved for treating social phobia. 2005). A 12-week extended-release venlafaxine study. 2005). and used in standard dosages comparable with those used in depression. A double-blind discontinuation study examined relapse in socially phobic patients initially treated openly for 12 weeks with escitalopram. 50–200 mg/day. performance. 2002a). In a 12-week study comparing 20. Stein et al. A 20-week treatment study with sertraline. 1998b). paroxetine at a dosage of 20 mg/day was found to be efficacious compared with placebo. 2002a. and 60 mg/day. 1995). A 12-week placebo-controlled trial of escitalopram. 2001). with a response rate of 78% and improvement in social anxiety. Newer antidepressants other than SSRIs are also efficacious in treating social phobia. with only 8% of patients discontinuing due to adverse events (Liebowitz et al. 40. 2005). 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. and lack of efficacy for comorbid depression. Efficacy for sertraline at dosages of 50–200 mg/day was shown in one placebo-controlled study (Katzelnick et al. 2005). but it may have some efficacy in social phobia (Emmanuel et al. with good tolerability (Rickels et al. with a 44% response rate and a 30% remission rate (Liebowitz et al. 2004). good tolerability. About one-half to two-thirds of patients studied responded to acute treatment at average dosages of about 40 mg/day. Stein et al. reported a 53% response rate with medication compared with 29% for placebo (Van Ameringen et al. and in one controlled study clonazepam at dosages of 0. B. using dosages of 75–225 mg/day. and clear advantages were not identified for the higher dosages in this study (Liebowitz et al. and found that the risk of relapse was almost three times higher in patients who discontinued active treatment (Montgomery et al. A placebo-controlled trial of mirtazapine in 66 women with social phobia also reported efficacy (Muehlbacher et al. avoidance. resulting in the SSRIs becoming the first-line treatment for the disorder. 2002b). M. with a 58% response rate and a 31% remission rate (M. Similar responses were found in an open trial of fluoxetine (Van Ameringen et al. with efficacy shown in several controlled trials (Baldwin et al. relapse. Alprazolam has also been found to be superior to placebo. the alprazolam group had the highest relapse rate 2 months after treatment discontinuation (C. 2. such as relatively rapid onset of action and good tolerability. 10–20 mg/day. clonazepam is a better choice than alprazolam. J. Stein et al. Similarly. 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. atenolol. and significant improvement in work and social impairment (Kasper et al. a 12-week venlafaxine extended-release study using flexible dosing (75–225 mg/day) reported superiority to placebo. Similarly. 10–20 mg/day. They are generally well tolerated. Gelernter et al. and negative self-evaluation (Davidson et al. (1992) conducted a controlled study comparing phenelzine. with many nonresponders at week 8 achieving response by week 12 (D. 1991). 2001). 1994). Benzodiazepines Benzodiazepines can also be helpful in treating generalized social phobia. The benzodiazepines would not be considered a first-line treatment for social phobia. Several open trials have reported positive results. Disadvantages are the potential for abuse. Both have advantages. replicated in a subsequent larger study with a comparable mean dosage of 200 mg/day and a response rate of 43% (M. withdrawal. B. reported efficacy with a 54% responder rate. Bupropion is the least studied antidepressant to date. 1991). despite the usual concerns about their chronic use.Newer antidepressants In the past decade. 2003). Stein et al. Given its longer half-life.5–3. B. 1999). with results comparable with those for phenelzine and CBT. A later large 20-week trial of sertraline versus placebo confirmed sertraline's efficacy. a 6-month double-blind. 2005).

2005a. work. and the frequently not-well-tolerated side effects. 1988). 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. rehearsal. TABLE 12–21. 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. A new medication approach specifically targeting axillary hyperhydrosis in socially phobic patients with excessive sweating appears promising. John's wort was no more effective than placebo in one study (Kobak et al. suggesting that in some patients who do not benefit adequately from antidepressant monotherapy. An open-label trial of quetiapine monotherapy in 13 patients with GAD. whereas atenolol was not superior to placebo. B. . S. benzodiazepines can lead to additional improvement (Seedat and Stein 2004). Social skills training employs modeling. 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. in practice they are often combined in order to attain a sufficiently satisfactory response. alprazolam. phenelzine tended to be superior in absolute clinical response and decreased impairment. Buspirone. 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. 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. treated for 12 weeks at a mean dosage of 250 mg/day. Cognitive and Behavioral Therapies Three major cognitive-behavioral techniques are used in the treatment of social phobia: exposure. Atypical antipsychotics have also received limited attention in treating social anxiety. St. reported a response rate of 70% (Schutters et al. role-playing. Stein et al. Cognitive and behavioral approaches to treating social anxiety disorder Exposure (imaginal and/or in vivo) Cognitive restructuring Social skills training (modeling. and overall disability (Connor et al. rehearsal. An open trial of topiramate. at dosages of 45–90 mg/day. with a response rate approaching 40% of subjects (Pande et al. the potential for hypertensive crises. A small placebo-controlled olanzapine trial found that olanzapine was superior to placebo (Barnett et al. cognitive restructuring. 1999). A placebo-controlled trial of the anticonvulsant gabapentin found it superior to placebo at a mean dosage of about 2. in dosages up to 30 mg/day. Pregabalin at a dosage of 600 mg/day was shown to be superior to placebo in a 10-week treatment of social anxiety disorder. therapeutic results are not gained until in vivo exposure to the real-life feared situations is done. the fear of negative evaluation by others. 2002). and placebo. Although all groups improved significantly with treatment. The anticonvulsant levetiracetam was not found to be efficacious in a pilot placebo-controlled study (Zhang et al. 1991) compared cognitive-behavioral group treatment with phenelzine. 2006a). Other medication options Although augmentations and combinations have not been systematically tested in clinical trials. Cognitive restructuring focuses on poor self-concepts. 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. at dosages of up to 400 mg/day. Despite their proven efficacy in social phobia. with an expectation that this will lead to more positive responses from others. reported benefit in treating social anxiety disorder (Van Ameringen et al. 2005). Gelernter et al. 2004). A pindolol augmentation study of SSRIs did not report additional benefit (M. whereas pregabalin at a dosage of 150 mg/day was not (Pande et al. and social skills training (Table 12–21).DSM-III social phobia. One study (C. 2001b). was not shown to be efficacious in a controlled study (van Vliet et al. About two-thirds of patients had a marked response to phenelzine. 2005b).900 mg/day. MAOIs are no longer a first-line treatment given their dietary and medication restrictions. a 5-HT1A agonist anxiolytic. role-playing. 1997). and assigned practice to help individuals learn appropriate behaviors and decrease anxiety in social situations. 2004a). 2005). social functioning.

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

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.

Psychodynamic Theory
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.

Behavioral Theories

it must be encoded by amygdala-based emotional memory but not by hippocampal-based episodic memory. biological. only a minority of individuals exposed to a certain stimulus develop a phobic reaction. a modified conditioning model would be needed. Models of the etiology of specific phobias have recently been elaborated and critiqued by Fyer (1998). This could be due to various processes such as stressful life events. one twin study did not support a genetic component to specific phobias.. However. the unconditioned stimulus). and insula in spider phobic individuals but not in control subjects. most phobias are resistant to extinction in the absence of specific interventions. very brief stimuli that can only be perceived implicitly—have lent partial support to the notion that phobic stimuli. Fourth.e. cingulate. as is found in panic disorder (Antony et al. and there is increasing evidence that the model also applies to specific phobias. can elicit a subjective or objectively measured fearful response (Van Den Hout et al. or unsafe environments.. suggesting environmental causation (Skre et al. and learning theory approaches. which is in a sense the converse of the conditioned model just described. The neurobiology of specific phobias has been studied more in the past several years. despite belief and evidence that there is nothing to fear. 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. whereas wider circuits involving the insula. Gelernter et al. This classical learning theory model of phobias has received much reinforcement from the relative success of behavioral (i. there was no increased risk for other comorbid phobic or anxiety disorders. conditioned response). . 2004).. many phobic patients do not recall an initial aversive event. on four counts. the noxious experience (e. An fMRI study examining spider phobia implicated the right amygdala in automatic stimulus processing. it turns out that a very small number of objects account for most of human phobias. discomfort. mediated by the amygdala.e. Phobia-related stimuli elicit heightened activation in the prefrontal cortex. If the individual frequently receives an electric shock when in contact with the phobic object. and dorsomedial prefrontal cortex were implicated in attentional processes involved in threat evaluation (Straube et al. Two studies examining response to CO 2 inhalation in subjects with specific phobia have found no differences from healthy subjects and no hypersensitivity. an electric shock) produces an unconditioned response of pain. suggesting that if such an event had occurred. 2004). suggesting visual and tactile imagery as one component of the phobic response. 2003). and fear.e. She concluded that in order to satisfactorily explain specific phobia. Third. Such a model is attractive in that it may account for the occurrence of such a highly fearful response to the conditioned phobic stimulus. Initially. then by contiguous conditioning the appearance of the phobic object alone may come to elicit an anxiety response (i. 1995). 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. 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.. with a roughly threefold risk for first-degree relatives of affected subjects. Fyer et al. Two studies reported activation of the visual associative cortex (Fredrikson et al. One whole-genome scan study implicated a chromosome 14 risk locus in simple phobia (J. suggesting that there may be an evolutionarily wired biological preparedness toward specific stimuli that would be easily conditioned but difficult to extinguish. Avoidance of the phobic object prevents or reduces this conditioned anxiety and is therefore perpetuated through drive reduction. 1997). deconditioning) techniques in the treatment of many patients with specific phobias. First. Biological Theories Some interesting hypotheses about the origin of phobias have resulted from integration of ethological. constitutional vulnerabilities. (1990) found high familial transmission for specific phobias. Brain imaging studies in specific phobias have begun to illuminate their neurocircuitry. Another model of specific phobias is the nonassociative learning model (Fyer 1998). Studies exposing specific phobia subjects to masked stimuli—that is. Second. the conditioned stimulus) with a noxious experience (i.In learning theory. anterior cingulate.e. sometimes without hippocampal or cortically based knowledge or memory of why there is such fear..g. 1997). phobic anxiety is thought to be a conditioned response acquired through association of the phobic object (i. However. because it either occurred before age 3 years or was encoded under highly stressful conditions. 1993) and of the somatosensory cortex (Rauch et al. suggesting that additional factors such as genetic vulnerabilities or previous experiences play a role. 1993). even when not consciously registered. The brain circuits mediating conditioned fear responses have emerged as central to the pathogenesis of a number of anxiety disorders.

antipanic medication may also be indicated. greatly facilitating the ease of administration of many in vivo–type exposures. 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. about half were clinically symptomatic at follow-up. Exposure can be accompanied by varying degrees and types of cognitive interventions that decatastrophize the phobic stimulus and encourage risk taking. whether intrinsically or as a result of treatment. and participant modeling and reinforced practice. Treatment The treatment of choice for specific phobias is exposure. Course and Prognosis Animal phobias usually begin in early childhood. In recent years. have been developed for those who are unable to travel due to their phobias (Kenwright and Marks 2004). In another study using fMRI before and after CBT. 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. TCAs. In other words. Most exposure techniques have been used in both individual and group settings. 2003). it appears that specific phobias follow a chronic course unless treated. Imaginal techniques confront the phobic stimulus through the therapist's descriptions and the patient's imagination. In a group setting. One virtual reality study of driving phobia reported positive results (Wald and Taylor 2003). in which 11 patients were randomized to either placebo or paroxetine up to 20 mg/day for 4 weeks. no significant activation was found in either brain region (Paquette et al.Imaging studies have been combined with treatment in order to examine the changes in brain activity that may mediate treatment response. whereas situational phobias tend to start later in adolescence or early adulthood. Although systematic prospective studies are limited. 1999a). Exposure treatments may be divided into two groups depending on whether exposure to the phobic object is "in vivo" or "imaginal. and -blockers generally do not appear useful for specific phobias based on the limited number of studies available to date." In vivo exposure involves the patient in real-life contact with the phobic stimulus. benzodiazepines. 2002). Ungraded exposure begins with the patients confronting the most stressful items in the hierarchy. 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. Techniques may include systematic desensitization. imaginal flooding. 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. this study suggests that specific phobias may be resistant to treatment or often do not receive treatment (Lipsitz et al. both the example and the encouragement of other members are often particularly helpful in persuading the patient to reenter the phobic situation. with brief telephone support from a therapist. after successful completion of CBT. 2006). Graded exposure uses a hierarchy of anxiety-provoking events varying from least to most stressful. and none of the patients who had not improved with the initial treatment were any better at follow-up. The patient begins at the least stressful level and gradually progresses up the hierarchy. in both groups activation of the prefrontal cortex varied with the capacity to self-regulate. including specific phobias. The method of exposure in both the in vivo and imaginal techniques can be graded or ungraded. 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. For those patients whose phobic symptoms include panic attacks. Those patients who managed to control their emotional reaction during spider exposure before treatment showed increased activation in the prefrontal cortex. promising computer-aided self-help exposure programs via the Internet. Similarly promising results were reported in a virtual reality treatment study of spider phobia (Garcia-Palacios et al. is the development of virtual reality exposure techniques. which permit "virtual exposure" in a clinical setting. Medications have not generally been shown to be effective in treating specific phobias. reported that one out of six patients responded to placebo and three out of five to paroxetine . prolonged in vivo exposure. One recent small controlled trial. aimed at fear extinction. phobic subjects before CBT showed dorsolateral prefrontal cortex activation. whereas after successful treatment they showed a decline in activation in this region. Another new and exciting development in the treatment of all phobias. In contrast. The problem lies in persuading the patient that exposure is worth trying and will be beneficial. 2002) and one of flying phobia (Banos et al. 2006). 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.

praying. gambling. 2004). 2005).g. when engaged in excessively may be referred to as "compulsive. At some point during the course of the disorder. repeating words silently) that the person feels driven to perform in response to an obsession. There has been a recent surge in interest in the combination of medication and exposure therapy. 2000). or drinking. the content of the obsessions or compulsions is not restricted to it (e. (3). hair pulling in the presence of trichotillomania. Obsessive brooding. or preoccupations. If another Axis I disorder is present. all subjects received two virtual reality exposure sessions and were premedicated with either D-cycloserine or placebo. DSM-IV-TR diagnostic criteria for obsessive-compulsive disorder A. a drug of abuse. or to neutralize them with some other thought or action (4) the person recognizes that the obsessional thoughts. including specific phobias.g. a 50-mg dose of D-cycloserine. sexual behavior.. (2). 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. or images that are experienced. or guilty ruminations in the presence of major depressive disorder).g. 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.. such as eating. a glutamatergic agent which at low dosages has NMDA receptor agonist effects and facilitates new learning.. Note: This does not apply to children. Specify if: With poor insight: if. is combined with exposure to further promote extinction. D. although possibly excessive and painful." these activities are distinguished from true compulsions in that they are experienced as pleasurable and ego-syntonic. the person has recognized that the obsessions or compulsions are excessive or unreasonable. C. which persisted at 3-month follow-up (Ressler et al. ruminations. concern with appearance in the presence of body dysmorphic disorder. . and (4): (1) recurrent and persistent thoughts. or images. 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. hand washing. preoccupation with food in the presence of an eating disorder. DSM-IV-TR criteria for OCD are presented in Table 12–23. TABLE 12–23. The disturbance is not due to the direct physiological effects of a substance (e. are time consuming (take more than 1 hour a day). counting. at some time during the disturbance. preoccupation with having a serious illness in the presence of hypochondriasis. Either obsessions or compulsions: Obsessions as defined by (1). although their consequences may become increasingly unpleasant and ego-dystonic over time. preoccupation with drugs in the presence of a substance use disorder. checking) or mental acts (e. 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. preoccupation with sexual urges or fantasies in the presence of a paraphilia. OBSESSIVE-COMPULSIVE DISORDER Definition The essential features of OCD are obsessions or compulsions.g. for most of the time during the current episode. or significantly interfere with the person's normal routine. impulses. as intrusive and inappropriate and that cause marked anxiety or distress (2) the thoughts. ordering. traditional or virtual reality. Similarly. typically characteristic of depression. In this treatment paradigm. in treating anxiety and fear. however. may be unpleasant but are distinguished from true obsessions because they are not as senseless or intrusive and the individual regards them as meaningful. In a treatment study of 28 patients with acrophobia (fear of heights). The obsessions or compulsions cause marked distress. 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. The combination treatment group manifested significantly greater improvement. a medication) or a general medical condition.(Benjamin et al. impulses. or images are not simply excessive worries about real-life problems (3) the person attempts to ignore or suppress such thoughts. Although some activities. E. occupational (or academic) functioning.. impulses. impulses.

Patients may spend many hours every day washing. Based on this. called "hoarders. and eating breakfast. abnormal birth events. An obsession is an intrusive. and after an insidious onset there is a chronic and often progressive course. break your mother's back. One group includes patients with obsessions about dirt and contamination.. 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). child molestation). However. blasphemy. Other common obsessional fears involve harm coming to oneself or to others as a consequence of the patient's misdoings. Clinical Description Onset OCD usually begins in adolescence or early adulthood but can begin prior to that time. and 3) OCD often occurs in association with other anxiety disorders. which are subsumed by the stress and fear circuitry.There are several presentations of OCD based on symptom clusters. ideas. compulsions decrease anxiety only transiently. or nonsensical content. excessive. and the nature of the fears in OCD is distinct from those of other anxiety disorders. Obsessions may be thoughts. the person does not recognize that the obsessions and compulsions are excessive or unreasonable. rape. which will be grappled with in DSM-V (Bartz and Hollander 2006).g. murder. 28% are bothered mainly by obsessions. various sources of evidence support this view. the DSM-IV specified a poor insight type if. convictions. and 50% by both (Foa et al. about 5% are convinced that their obsessions and compulsions are reasonable. it has been disputed whether OCD belongs with the rest of the anxiety disorders. no particular stress or event precipitates the onset of OCD symptoms. without being caused by an emotional or affect-like state. and inconclusive thinking about metaphysical questions. are intended to reduce anxiety or prevent harm. 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. OCD is classified among the anxiety disorders because 1) anxiety is often associated with obsessions and resistance to compulsions. like behavioral compulsions. whereas obsessional images are often vivid visual experiences. The person may think of doing the worst possible thing (e. In DSM-IV-TR. Obsessional convictions are often characterized by an element of magical thinking. Although most patients have some degree of insight. or in a separate grouping of compulsive spectrum disorders. for most of the time during the current episode. with 75% developing OCD by age 30. Even though obsessions are typically experienced as ego-dystonic. Mental rituals are encountered in the great majority of OCD patients and. ruminations. There is evidence of OCD associated with the 1920s encephalitis epidemic. disgusting." Obsessional ruminations may involve prolonged. Obsessional impulses may be aggressive or sexual. such as one's home catching on fire because the stove was not checked or running over a pedestrian because of careless driving." are unable to throw anything out for fear they might someday need something they discarded. Some OCD patients. and life goes on at an extremely slow speed. and onset following head injury or seizures. More recently. In most cases. Primary obsessional slowness is evident in another group. Of interest are reports of new onset of OCD during pregnancy (Neziroglu et al. or impulses and are often of an aggressive. However. Obsessional thoughts were defined by Karl Westphal in 1878 as ideas that in an otherwise intact intelligence. A second group includes patients with pathological counting and compulsive checking. in whom slowness is the predominant symptom. DSM-IV also made explicit that compulsions can be either behavioral or mental. getting dressed. Obsessional ideas are repetitive thoughts that interrupt the normal train of thinking. This is particularly true of patients with a neurological basis for their illness. and against the will of the person come into the foreground of the consciousness (Westphal 1878). 1992). Although over 90% of patients have features of both obsessions and compulsions. 1995). Much obsessive thinking involves horrific ideas. 2) anxiety or tension is often immediately relieved by yielding to compulsions. 20% by compulsions. Obsessional fears often involve dirt or contamination and differ from phobias because they are present in the absence of the phobic stimulus. such as . images. fears. there is a wide range of insight in patients with OCD. unwanted mental event usually evoking anxiety or discomfort. sexual. 31% of first episodes occur between ages 10 and 15 years. whose rituals center around compulsive washing and avoidance of contaminated objects. religious. such as "step on the crack. some patients describe a sudden onset of symptoms. A third group includes purely obsessional patients with no compulsions.

in some cases. for example. In the DSM-IV OCD field trials. Attributing these obsessions to an internal source. However. or germs and may spend many hours a day washing their hands or showering. and hoarding (Leckman et al. these subtypes may prove useful in the future when examining possible genetic. paranoia. 80% of patients had both behavioral and mental compulsions. and being meticulous. neurobiological. and control is the patient's actual success in diverting his or her thinking. those who are purely obsessional. 1975. cleanliness and washing. 1975. Obsessions are usually accompanied by compulsions but may also occur as the main or only symptom.000 patients identified the same four consistent "syndromes": symmetry/ordering. Although distinct symptom clusters exist (washers. may actually exacerbate it. parsimony. 1997). punctuality. avoiding. symmetry and ordering. contamination/cleaning. When patients with obsessional traits decompensate. 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. Similarly. a more recent meta-analysis of several factor-analytic studies involving more than 2. or treatment-response heterogeneity in OCD. who manifest premature certainty. checkers. OCD) symptoms and personality traits such as obstinacy. contaminants. Rachman and Hodgson 1980). these symptoms may overlap or develop sequentially. In the DSM-IV field trial. may replay over and over in their minds past conversations with others to make sure they did not somehow incriminate themselves. Compulsions A compulsive ritual is a behavior that usually reduces discomfort but is carried out in a pressured or rigid fashion. Freud (1913/1958) noted an association between obsessional neurosis (i. and mental compulsions were the third most common type after checking and washing. OCD symptoms are ego-dystonic. urine. and significant impairment in functioning can result. for example. Such behavior may include rituals involving washing. Although slowness results from most rituals. Washers represent about 25%–50% of most OCD samples (Akhtar et al. Mental compulsions are also quite common and should be inquired about directly. Character Traits Psychoanalytic theorists have suggested that there is a continuum between compulsive personality and OCD. Such patients. In contrast to manic or psychotic patients. Therefore. Approximately 10%–25% of OCD patients are purely obsessional or predominantly experience obsessions (Akhtar et al. whereas obsessive-compulsive personality traits are ego-syntonic and do not involve a sense of compulsion that must be resisted against. "Checkers" have pathological doubt and thus compulsively check to see if they have. These four syndromes can coexist in any one patient and be continuous with more normative obsessive-compulsive phenomena. These individuals are concerned with dirt. it is the major feature of the rare and disabling syndrome of primary obsessional slowness. Epidemiological studies show that obsessive-compulsive character pathology is neither necessary nor sufficient for the development of OCD symptoms.intrusive impulses of stabbing one's spouse or raping one's child.e. washing and checking were the two most common groups of compulsions. These patients may have little anxiety despite their obsessions and rituals. and obsessions/checking (Mataix-Cols et al. phenomenological and epidemiological evidence suggests that OCD is frequently distinct from obsessivecompulsive personality disorder. 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. checking. repeating. or vaginal secretions. OCD patients are unable to achieve a sense of certainty between incoming sensory information and internal beliefs. hoarders. This slowness may be a response to a lack of certainty as well. they often develop depression. or somatization rather . They may also attempt to avoid contaminating themselves with feces.. hoarding. striving for completeness. the patient resists or controls them to a variable degree. It may take several hours for the obsessionally slow individual to get dressed or get out of the house. Resistance is the struggle against an impulse or intrusive thought. Rachman and Hodgson 1980). Another hallmark of obsessive thinking involves lack of certainty or persistent doubting. Checking often fails to resolve the doubt and. 2005). because they could go undetected if the clinician only asks about behavioral rituals. run over someone with their car or left the door unlocked. and those with primary slowness). and orderliness. Janet (1908) stated that all obsessional patients have a premorbid personality that is causally related to the disorder.

undoing. 1982). 1992. about 8% met criteria for OCD. no OCD was detected in relatives of probands with onset after age 18 (Nestadt et al. Obsessive-compulsive patients are thought to utilize the defense mechanisms of isolation. and it may suggest partly differing etiologies or vulnerabilities in the two sexes. A real or . fantasies. only a minority of OCD patients had DSM-III-R obsessive-compulsive personality disorder. Studies of first-degree relatives of OCD patients show a higher-than-expected incidence of a variety of psychiatric disorders. including obsessive-compulsive symptoms. eating disorders. a 6-month prevalence of 1. Family studies have also shown that OCD spectrum disorders. There are reports demonstrating comorbidity of OCD with schizophrenia. that there may exist a more strongly familial subtype of OCD with an earlier onset. and the finding was more robust for obsessions. or gesture.than OCD. The fixation is presumably due to excessive investment in anal eroticism resulting from excessive frustrations or gratifications in the anal phase. and ambivalence to control unacceptable sexual and aggressive impulses. occur more frequently than expected in the relatives of those with OCD (Bienvenu et al. and grooming conditions. This study suggests. Black et al. suggesting they could be secondary to the Axis I disorder. 1988). 2006). personality disorders may be more common in the presence of a longer duration of OCD. In a clinical sample of schizophrenic and schizoaffective patients. Black 1974). Isolation Isolation is an attempt to separate the feelings or affects from the thoughts. In addition. In more recent standardized evaluations. Epidemiologically. Carey and Gottesman 1981). Another recent study supports that there may exist a familial spectrum of OCD and obsessivecompulsive personality disorder (Samuels et al. age at onset of OCD in probands was very strongly related to familiality. and Tourette's syndrome. 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 have been no studies of OCD in adopted children or monozygotic twins raised apart. and criteria for personality disorders may no longer be met after successful treatment of the OCD (Baer and Jenike 1992). eating disorder. A recent large family study found that OCD was about fourfold more common in relatives of OCD probands than in control relatives.3%. Epidemiology The ECA study (described earlier in this chapter) suggested that OCD is quite common. there is a roughly equal ratio of men to women (A.5%. An example is a patient who describes a particularly gruesome thought or fantasy but denies any feelings of anxiety or disgust associated with it. about 70% of patients are male (Swedo et al. depression. reaction formation. such as body dysmorphic disorder. G. and regression. W. However. Undoing Undoing is an attempt to magically reverse a psychological event. 1989b). In this model.5% (Regier et al. such as a word. autism. These defense mechanisms are unconscious and thus not readily apparent to the patient. highlighting the importance of screening for obsessive-compulsive symptoms in such populations where detection may be more difficult (Eisen et al. Carey and Gottesman 1981). 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. as does a similar one in panic disorder. 1988). Family studies suggest a genetic link between OCD and Tourette's syndrome (Nee et al. In clinical samples of adult OCD. thought. 1997). with a 1-month prevalence of 1. in childhood-onset OCD. Interestingly. structured personality assessments were not used. This difference seems to be accounted for by the earlier age at onset in males. 2000). and a lifetime rate of 2. obsessive-compulsive pathology involves fixation and subsequent regression from the oedipal to the earlier anal developmental phase. anxiety disorders. hypochondriasis. other anxiety disorders such as panic disorder and simple and social phobia. or impulses associated with them. suggesting that some predisposition to obsessional behavior is inherited. the OCD comorbidity risk for other major psychiatric disorders was found to be fairly high but nondistinctive (Karno et al. Although the older literature suggested the presence of definite obsessional traits in as many as two-thirds of OCD patients. and depression (D. whereas other personality disorders such as avoidant or dependent were more common (Thomsen and Mikkelsen 1993). 2000b).

classical conditioning). 1999). anxiety is classically conditioned to a specific environmental event (i. order. because the person avoids the eliciting stimulus and thus avoids extinction. resulting in displaced ambivalence and paralyzing doubts. and loving feelings predominate toward significant objects. and parsimony. If the individual is successful in reducing anxiety. control.e. may be a key factor influencing obsessive behavior (Salkovskis et al. Higher-order conditioning occurs when other neutral stimuli such as words. regression is theorized to take place from the genital oedipal phase to the earlier pregenital anal-sadistic phase.imagined act can be undone by evoking its opposite. Taylor et al. TABLE 12–24. aggressive impulses are neutralized. Subjects with OCD also appear to have memory biases toward disturbing themes. 1997). Regression In OCD. and it has been proposed that such deficits may relate to their diminished ability to selectively ignore intrusive cognitive stimuli (Clayton et al. perfectionism and intolerance of uncertainty. images. Biological models of obsessive-compulsive disorder Serotonergic dysregulation Additional dopaminergic dysregulation. Biological Theories Although OCD used to be viewed as having a psychological etiology. People with OCD have been found to have deficits in selective attention. better memory for contaminated objects than control subjects with comparable memory (Radomsky and Rachman 1999). anxiety reduction after the ritual preserves the compulsive behavior. somatostatin) Hyperactive orbitofrontal–limbic–basal ganglia circuitry . 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). then at least to the maintenance of the disorder. Three main types of dysfunctional beliefs have been identified in OCD: responsibility and overestimation of threat. Individuals with OCD who "check" have been found not to have memory impairments that presumably could account for the increased checking. Thus. Themes characteristic of the anal phase typically reflect conflicts surrounding ambivalence. for example. at least in subgroup of patients Neuropeptide abnormalities (oxytocin. vasopressin. or thoughts are associated with the initial stimulus and the associated anxiety is diffused. such that thoughts of harming someone become confused with action and may lead to a sense of uncertainty over actually having harmed someone. strong aggressive impulses are thought to reemerge toward love objects. 2000). and importance and control of thoughts (S.. Certain types of cognitions and cognitive processes are highly characteristic of OCD and presumably contribute. 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. In Stage 1. which has not been fully relinquished. In particular. dirt. the characteristic thought omnipotence results in magical ideation and lack of certainty. Ritualized behavior preserves the fear response. but rather. they have decreased confidence in their memory (MacDonald et al. In OCD. such as turning on and then turning off a light switch. The person then engages in compulsive rituals (escape/avoidance responses) in order to decrease anxiety. Likewise. 2005). negative beliefs about responsibility. Ambivalence In normal development. especially responsibility surrounding intrusive cognitions. 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). if not to the genesis. the compulsive behavior is more likely to occur in the future (Stage 2: operant conditioning). This regression helps the patient avoid genital conflicts and the anxiety associated with them. 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. In addition. Reaction formation The defense of reaction formation substitutes an unacceptable unconscious impulse with its opposite.

1994). 2005). 1999). Basal ganglia abnormalities were particularly suspected in the pathogenesis of OCD. smaller globus pallidus and increased anterior cingulate cortex (Szeszko et al. J. Swedo et al. Along the lines of this model. although not always consistent. repetitive.Autoimmune streptococcal-related component in some individuals Genetic component. Rauch et al. based on the hypothesized orbitofrontal–limbic–basal ganglia dysfunction. whereas the accompanying anxiety is reflected by activity in the hippocampus and cingulate cortex (McGuire et al. Kim et al. and processing speed. increased volume of the orbitofrontal cortex and thalamus (J. This could be due to a heightened internal drive state or an increased responsivity to external releasers. 1994). Using emotional Stroop tasks. cingulate cortex. With fMRI. leading to the inability to inhibit unwanted verbal-ideational mental representations and their corresponding motor sequences. (1989c) showed higher metabolic activity in the orbitofrontal and cingulate regions in OCD. A particular B lymphocyte antigen. 2001). 1989a). and reduced amygdala (Pujol et al. OCD patients displayed specific neural responses to OCD-related words. ? 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. Volumetric imaging studies have consistently revealed abnormal volumes in the implicated circuit. increased putamen. and excessive. 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). neurological. and orbitofrontal cortex relative to the resting state (Adler et al. including reduced orbitofrontal and amygdala volumes (Szeszko et al. significant increases in relative blood flow occur in "real" time in the caudate. 1987) compared OCD patients and normal control subjects using PET and found higher metabolic rates in the orbitofrontal gyri and caudate nuclei in OCD. and have suggested abnormalities in memory. A certain form of OCD with childhood onset is believed to be related to an autoimmune process secondary to streptococcal infection. Similarly. which can be identified by the monoclonal antibody D8/17. abnormalities on the electroencephalogram. 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. 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. 2005). and their group (Swedo 1989. enlarged thalamus (Gilbert et al. trial-and-error learning. OCD behaviors such as excessive washing or saving may be dysregulated manifestations of normal grooming or hoarding behaviors. 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. 2004). In such children. suggesting that D8/17 may serve as a marker for susceptibility to childhood-onset OCD (Murphy et al. More recently. 2000). 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. an association with diabetes insipidus. smaller basal ganglia (Rosenberg et al. 1997). or streptococcal control subjects (Dale et al. and ventricular brain ratio on computed tomography scan. memory confidence. Neuropsychological findings in OCD are also of some interest. as well as with Sydenham's chorea. 1986). It has been suggested that the severity of obsessive urges correlates with orbitofrontal and basal ganglia activity. 2005). For example. 2000). in which basal ganglia dysfunction results in abnormal involuntary movements. enlarged basal ganglia have been found on magnetic resonance imaging scans. a high incidence of neurological premorbid illnesses in OCD. Baxter et al. Swedo. such children have also been found to have elevated anti–basal ganglia antibodies compared with pediatric autoimmune. which is consistent with an autoimmune hypothesis (Giedd et al. given that OCD is closely associated with Tourette's syndrome (Pauls et al. 1997). Breiter et al. Flor-Henry (1983) hypothesized that the fundamental symptomatology of obsessions was due to a defect in neural inhibition of dominant frontal systems. with increased . and the presence of significantly more neurological soft signs in OCD patients compared with healthy control subjects. Such findings include the onset of OCD following head trauma or von Economo's disease. Wise and Rapoport 1989). 2000. it has been possible to demonstrate that during the behavioral provocation of symptoms in OCD patients. Neuroanatomy and Functional Neurocircuitry A neuroethological model of OCD has been proposed by Rapoport. a plethora of neuroimaging studies have yielded a sophisticated neuroanatomical underpinning for OCD. reduced orbitofrontal cortex gray matter. and increased orbitofrontal and decreased anterior cingulate gray matter (Valente et al. specifically implicating orbitofrontal–limbic–basal ganglia circuits. Obsessions and compulsions are conceptualized as species-specific fixed action patterns that are normally adaptive but in OCD become inappropriately released. 2004). 1996. an association of OCD with birth trauma. another disorder of the basal ganglia (Swedo et al. auditory evoked potentials.

2005). reduction of OCD symptoms during clomipramine treatment was shown to correlate with a decrease in platelet serotonin level (Flament et al. Deficient sensorimotor gating. Furthermore. associated with frontostriatal dysfunction. White matter abnormalities in the anterior cingulate have also been implicated in OCD. an acute tryptophan-depletion study in SSRI-treated and remitted OCD patients failed to provoke OCD symptom exacerbation. and thalamus (Saxena et al. 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. Perani et al. Deficits in executive function planning. 2005). Hollander et al. There is also some evidence that different OCD symptom dimensions (washing. supports the model of deficient frontostriatal circuits in OCD (Hoenig et al. 1992). . 2000). a decrease in initially abnormally large thalamic size has been imaged after successful response to paroxetine treatment (Gilbert et al. hyperactivity decreases in the caudate. there was decreased activation of the prefrontal and cingulate cortex under symptom provocation (Nakao et al. Swedo et al. 2005b). orbitofrontal lobes. suggesting a decoupling of malfunctioning brain circuits (J. 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. 1992) but not others (Zohar et al. Increased 5-HT2A receptor binding has been reported in the caudate nuclei of OCD patients. and ipsapirone. 1992. suggesting defects in connectivity of the cingulate with other regions involved in the OCD circuitry (Szeszko et al. such as tryptophan. 2005). 1988). 2004). Other serotonin agonists. After treatment of OCD with serotonin reuptake inhibitors or behavior therapy. Dysregulation of this behaviorally inhibitory neurotransmitter possibly contributes to the repetitive obsessions and ritualistic behaviors seen in OCD patients. Also. or antagonists. irrespective of state symptomatology (van den Heuvel et al. such as metergoline. The use of pharmacological challenge agents to stimulate or block serotonin receptors has also proved a fruitful technique in elucidating the neurochemistry of OCD. OCD patients show greater activation of the anterior cingulate in tasks involving error processing (Fitzgerald et al. A blunted prolactin response to m-CPP challenge has also been found in OCD patients by some investigators (Charney et al. 1987) and in CSF 5-hydroxyindoleacetic acid (Swedo et al. extensive research has now clearly implicated the serotonergic system in the pathogenesis of OCD. 2006). In another study. fenfluramine. a partial serotonin agonist. 2005). checking. social dominance. 1995. Neurochemistry Parallel to the functional neuroanatomy. Considerable indirect evidence supporting the role of serotonin in OCD stems from the well-documented antiobsessional effects of potent serotonin reuptake inhibitors. after successful behavioral treatment the correlations in brain activity between the orbital gyri and the caudate nucleus decrease significantly. only OCD treatment was associated with significant metabolic decreases in the caudate. 2002). Schwartz et al. 1991a. 2005a). m-CPP challenge no longer induced symptom exacerbation (Hollander et al. Interestingly. In summary. In children with OCD. Despite some conflicting and nonreplicated data. successful SSRI treatment of OCD or major depression resulted in cerebral activity changes that were disorder specific rather than treatment specific. Zohar et al. as measured via the prepulse inhibition paradigm. aggression. have not been shown to induce consistent behavioral or neuroendocrine response abnormalities in patients with OCD. have also been found in OCD. 2002). and hoarding) are mediated by relatively distinct components of the frontostriatothalamic circuits (Mataix-Cols et al. More recently. the neurochemistry of OCD has become extensively elaborated.activation of frontostriatal and temporal regions (van den Heuvel et al. in contrast to its mood-worsening effect. 2000). and learning. 1988). Oral m-CPP. Serotonin has been implicated in mediating impulsivity. 1996). after improvement of OCD with SSRI or behavioral therapy. suggesting that obsessive-compulsive symptoms are not dependent on short-term presynaptic serotonin availability (Berney et al. M. 1992b). suicidality. 2005). orbitofrontal cortex. and of the SSRIs in contrast to the ineffectiveness of noradrenergic antidepressants such as desipramine. and cingulate cortex in those patients who have good treatment responses (Baxter et al. suggestive of diminished serotonin transmission in the corticostriatal loop (Adams et al. 1988. 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. has been found to transiently exacerbate obsessive-compulsive symptoms in a subgroup of OCD patients (Hollander et al. such as clomipramine. 1992a). anxiety. After treatment of OCD with serotonin reuptake blockers such as clomipramine or fluoxetine. 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.

the dopamine D4 receptor gene (Millet et al. 2000). 1992a). 2005a). 1997). In a putative rat model of OCD. 2002. and the acquisition and maintenance of conditioned perseverative behaviors. the dopamine D2/D3 receptor agonist quinpirole has been shown to induce compulsive checking in specific locations of an open field (Dvorkin et al. and genomewide linkage studies have provided evidence for linkage on chromosome 9p (Hanna et al. 1991b) or orally (Knesevich 1982). 2003). and magnetic resonance spectroscopy studies have shown elevated glutamate levels in several regions involved in the hyperactive corticostriato-limbic-thalamic circuitry (Pittenger et al. more recently. and 54%–61% have a constant or progressive course (A. and decreased dopamine D2 receptor binding in the caudate nucleus of OCD patients (Denys et al. and have high celibacy rates (particularly in males) and a low fertility rate. the tryptophan hydroxylase gene (Han et al.8. Candidate genes that have been implicated to date include the GABA type B receptor 1 gene (Zai et al. 2001. the dopamine transporter and dopamine D4 receptor genes (Frisch et al. then. J. 2000). an association between higher pretreatment CSF homovanillic acid and good treatment outcome (Swedo et al. 2005). 2006). Black 1974. All these neuropeptides may be implicated in arousal. 1994). CSF somatostatin (Altemus et al. the 5-HT2A receptor gene (Enoch et al.It also does not appear that serotonergic dysregulation alone can fully explain the neurochemistry of OCD. TABLE 12–25. Meira-Lima et al. 2006). Course and Prognosis Studies of the natural course of the illness suggest that 24%–33% of patients have a fluctuating course. With clomipramine treatment. 1999. It is possible that the serotonergic system may. be modulating or compensating for other dysfunctional neurotransmitter systems or neuromodulators. and the glutamate NMDA receptor gene (Arnold et al. 2006). Chabane et al. depression and anxiety are common complications of OCD. 2005). the glutamate kainate receptor GRIK2 gene (Delorme et al. Although prognosis of OCD has traditionally been considered to be poor. 2004). Similarly. 2006). blunted growth hormone response to the dopamine agonist apomorphine (Brambilla et al. genes predisposing to OCD have not been consistently identified to date. The disorder usually has a major impact on daily functioning. the catechol-O-methyltransferase (COMT) gene (Karayiorgou et al. 1999) and negative (Billet et al. CSF glutamate was found to be significantly elevated in medication-naive adult OCD subjects compared with control subjects (Chakrabarty et al. 2000). 1994) have been implicated in OCD. Of late. 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. 1992a). use of dopamine blockers to augment partial treatment response with serotonin reuptake blockers (McDougle et al. Table 12–25). the 5-HT2C receptor gene (Cavallini et al. with new developments in behavioral and pharmacological treatments this prognosis is now considerably improved. 2004). 1990) through the association between OCD and Tourette's syndrome. 1990). Abnormalities in CSF vasopressin (Swedo et al. memory. there has been increased interest in possible glutamatergic dysregulation in OCD. Hu et al. Findings regarding the serotonin transporter gene have been both positive (Bengel et al. Genetics Segregation analyses have provided support for a single major gene involvement in OCD (Alsobrook et al. 2000). 1992). Kim et al. Course and prognosis of obsessive-compulsive disorder Course Less than 15% phasic with periods of complete remission . although other noradrenergic challenge findings have been negative (Lucey et al. 2004). Patients are often socially isolated. and CSF oxytocin (Leckman et al. marry at an older age. 2000a). The noradrenergic 2 agonist clonidine has been reported to induce a transient improvement in OCD symptoms when administered to patients intravenously (Hollander et al. 1997. 2000). 1998. 1999. Frisch et al. 2004b). or the brain-derived neurotrophic factor gene (Zai et al. with some patients spending many waking hours consumed with their obsessions and rituals. Frisch et al. Various neuropeptide abnormalities have started to be elucidated in the past few years. 2005b). Willour et al. No associations were shown with mutations of the 5-HT2B receptor gene (S. 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. Compounding the situation. 1999). in part. reports of exacerbation of obsessive-compulsive symptoms with chronic stimulants. 11%–14% have a phasic course with periods of complete remission. 1993). 2004. 1997. In summary. Nestadt et al. the 5-HT1D receptor gene (Mundo et al. 2004). Dopaminergic dysregulation has been variously implicated in OCD (Goodman et al. Lochner et al. CSF levels of vasopressin and somatostatin tend to decrease while oxytocin increases (Altemus et al.

Diagnosis Although a variety of biological and neuropsychiatric markers have been associated with OCD. OCD patients may. 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. Importantly. decline. a more chronic course at baseline. and obsessions in 12% of cases may become delusions. having both obsessions and compulsions. are time consuming. Findings were more optimistic than expected. with chronic debilitation. thoughts about food in the presence of an eating disorder or guilty thoughts in the presence of major depression). In terms of acute treatment. Sometimes it is difficult to distinguish between an obsession (e. Differential Diagnosis The differential diagnosis of OCD is summarized in Table 12–26. the OCD symptoms must not be just secondary to another disorder (e.g. the presence of hoarding obsessions and compulsions is associated with poorer response to both medication treatment (Mataix-Cols et al. from approximately the 1950s to the 1990s (Skoog and Skoog 1999). An obsession is typically ego-dystonic. Yet longitudinal studies show that OCD patients are not at increased risk of developing schizophrenia. the presence of significant obsessive-compulsive symptoms in a . or severe obsessive-compulsive personality disorder. 2006)... and DSM-IV-TR allows the diagnosis of both disorders. or interfere with social or occupational functioning.g.. poorer social functioning at baseline. Thus. Both disorders may exist independently.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. however lack insight. and profound impairment in social and occupational functioning. Although all other Axis I disorders are allowed to be comorbidly present. 1999) and CBT (Rufer et al.g.. DSM-IV-TR defines OCD as the presence of either obsessions or compulsions that cause marked distress. A delusion is not resisted and is believed to be external. resisted. about half were fully or almost fully recovered. Of those. the diagnosis rests purely on the psychiatric examination and history. but occasionally it can be more difficult to distinguish OCD from depression. predictors of worse outcome were earlier onset. The diagnosis is usually clear-cut. contamination) and a delusion (e. 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. and having magical symptoms.g. and recognized as having an internal origin. psychosis. TABLE 12–26. phobias. with improvement noted in 83% of individuals. being poisoned).

What was previously thought to be a rare. TABLE 12–27. Unlike with panic disorder patients. appear to have increased comorbidity with simple and social phobia and panic disorder (Rasmussen and Tsuang 1986). The pharmacological approach to treatment of OCD is summarized in Table 12–27. may have small superiority over SSRIs. agitated depression. Patients with OCD who experience high levels of anxiety may describe panic-like episodes. three negative Lithium: ineffective in controlled trial Trazodone: ineffective in controlled trial Monoamine oxidase inhibitors: hardly any evidence. 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. sertraline: efficacy shown in large controlled trials Paroxetine. and difficult-to-treat illness now appears to have a strong biological component and to respond well to potent serotonin reuptake blockers. typically not used until at least two SSRIs have failed secondary to side-effect profile." Both have avoidant behavior. comorbid very high anxiety Buspirone: one positive trial. Atypical antipsychotics: several studies show additional benefit Pindolol: effective in controlled trial Clonazepam: effective in controlled trial. citalopram: less studied. and these patients may be difficult to distinguish from depressed patients who have complicating obsessive symptoms. both show intense subjective and autonomic responses to focal stimuli. there is no precipitation of anxiety attacks with lactate infusions in OCD patients (Gorman et al. moderate to high dosages. clomipramine plus desmethylclomipramine levels must be closely followed for toxicity Venlafaxine. Also. and both are said to respond to similar behavioral interventions. but these are secondary to obsessions and do not arise spontaneously. Patients with psychotic depression. Fluoxetine. whereas phobic patients have more focal. Phobic disorders A close connection exists between OCD and phobic and anxiety disorders. are often focused on a past incident rather than a current or future event and are rarely resisted. OCD does. OCD patients who are compulsive cleaners appear very similar to phobic individuals and are often mislabeled "germ phobics. presence of other target symptoms. can be used in low dosages in combination with SSRIs in patients with more refractory illness. OCD patients can never entirely avoid the obsession. similar efficacy Clomipramine: efficacy shown in multiple controlled trials. Both have excessive fear. but the distinction between primary and secondary obsessions rests on the order of occurrence. Depression Patients with OCD frequently have complicating depression. although disgust is prominent in OCD patients and not in phobic patients. fluvoxamine. These "secondary" obsessions often involve aggressive themes. external stimuli that they can successfully avoid. possibly phenelzine in symmetry obsessions Topiramate Riluzole Other medications . Pharmacological treatment of obsessive-compulsive disorder Serotonin reuptake inhibitors General indications: First-line treatments.schizophrenic patient warrants separate treatment. depressive ruminations. 1985). In addition. however. or premorbid obsessional features prior to depression are particularly likely to develop obsessions. in contrast to pure obsessions. psychodynamically laden. mirtazapine: less studied Augmentation strategies General indications: Partial response to serotonin reuptake inhibitors. however.

2001). in contrast to behavioral treatments. insomnia. Fluoxetine has been shown to be superior to placebo in treating OCD at dosages of 20–60 mg/day. 1998b). 2001). A series of well-controlled. 2002b). Some patients are unable to tolerate the highest dosage and may be stabilized at 150 mg or 200 mg. Clomipramine is equally effective for OCD patients with pure obsessions and those with rituals. 1995a. was superior to placebo. 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 .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. 2003c. with greater efficacy at higher dosages (Montgomery et al. Patients should typically be started on 25 mg of clomipramine at nighttime. and 60 mg/day. have no therapeutic effect. The medication was overall well tolerated. A multicenter trial reported that citalopram treatment. which are less useful for patients who predominantly experience obsessions. and the medication was well tolerated in the pediatric group. A multicenter randomized. controlled trial demonstrated efficacy for paroxetine in children and adolescents with OCD (Geller et al. Paroxetine and citalopram are also efficacious in treating OCD. with maximal response occurring after 5–12 weeks of treatment. 1994). Again. but not the 20 mg/day group. a potent serotonin reuptake inhibitor with weak norepinephrine reuptake blockade. 1999). The very low placebo response rate of 2% documents that OCD is a chronic disorder with infrequent spontaneous remissions. 40. and the MAOI clorgyline. asthenia and insomnia were the most common side effects (Riddle et al. nausea. 1990). sedation. 1993. Serotonin reuptake inhibitors The most extensively studied medication for the treatment of OCD is clomipramine. 2004). desipramine. and 42% of children were significantly improved after 12 weeks. and ejaculatory failure in men. The largest of these was a multicenter trial comparing clomipramine with placebo in more than 500 patients with OCD. generally at dosages of 20–60 mg/day. improvement started to appear around the third week. 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. without significant differences between the three dosages. Similarly. One issue with SSRI treatment is how high to push the dosage. On an average dosage of 200–250 mg/day of clomipramine. Controlled studies have also demonstrated that clomipramine is effective in treating OCD when other antidepressants. 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. 1994). nortriptyline. in dosages of 20. and tremor (March et al. 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. 2003a). such as amitriptyline. improved significantly more than placebo (Hollander et al. Numerous controlled trials since the early 1990s have documented the efficacy of all SSRIs for OCD. double-blind studies have undisputedly documented the efficacy of clomipramine in reducing OCD symptoms. The efficacy of fluvoxamine for OCD has also been demonstrated for children and adolescents (Apter et al. nausea. In this trial. Jenike et al. Improvement with clomipramine is relatively slow. although the highest response rate of 65% occurred in the 60 mg/day group (Montgomery et al. in an attempt to get a response. A multicenter paroxetine trial found that the 40 mg/day and 60 mg/day groups. Similarly. beyond the standard recommended OCD treatment dosage. Some of the more common side effects reported by patients are dry mouth. defined as a 25% symptomatic improvement. 1999). Response began to appear as early as the third week of treatment and was firmly apparent by the eighth week (Kronig et al. 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. the most common side effects were agitation. Fluvoxamine has also been found to have a significant antiobsessional effect in several controlled studies (Hollander et al. the average reduction in OCD symptoms was about 40%. SSRIs = selective serotonin reuptake inhibitors. fluoxetine has been shown to be safe and efficacious in treating OCD in children (Liebowitz et al. The required daily dosage is titrated up to a maximum of 300 mg. This finding strongly suggests that improvement in OCD symptoms is mediated through the blockade of serotonin reuptake. 42% of subjects were responders. Kronig et al. tremor. 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. and about 60% of all patients were clinically much or very much improved (Clomipramine Collaborative Study Group 1991). Tollefson et al.

have not been conducted. Given the similar efficacy of these five medications for OCD. Open-trial monotherapy followed by double-blind discontinuation of mirtazapine. and these have supported a small but significant superiority for clomipramine over the SSRIs (Greist et al. it is useful to remember that approximately 40%–60% of OCD patients improve by about 30%–60% with a first-line drug. 1992). 2004). Antipsychotics are the main medication class used to augment partial response to serotonin reuptake blockers in OCD. however. 1991). balancing benefits and side effects. In a small open trial. various combination and augmentation strategies are often needed to attain a satisfactory response. 1997). atypical antipsychotics. these strategies are worth undertaking sequentially. in dosages of 30–60 mg/day. Despite its putative serotonergic properties. given the relatively limited treatment options. comorbid tic disorders or schizotypal personality predicted a good response. they often do not look as promising as was initially thought. 1991). 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. (1990) first reported that about 50% of OCD patients improved noticeably when pimozide was added to fluvoxamine. and have therefore become the well-established first line of treatment for OCD. Piccinelli et al. 10 OCD patients who had failed to respond to serotonin reuptake inhibitor trials were treated with inositol augmentation. reported that about two-thirds responded to venlafaxine at a mean dosage of about 225 mg/day (Hollander et al. 1995. 2004). inositol. and clonazepam may also be helpful with the very high anxiety levels frequently associated with OCD. 1992b). for example. be limited. A controlled crossover study showed clonazepam to be effective in 40% of OCD subjects who failed to respond to clomipramine trials (Hewlett et al. three other studies failed to show a significant benefit to buspirone augmentation in clomipraminetreated (Pigott et al. augmentation with clomipramine or switching to clomipramine alone should be undertaken. about two-thirds of whom had not responded to SSRIs. 1992). 2005). showed preliminary evidence of efficacy that awaits larger replication (Koran et al. Although an initial small study reported similar efficacy for clomipramine alone versus buspirone alone in treating OCD (Pato et al. clonazepam. 2003b). 1995). and glutamatergic agents. A placebocontrolled augmentation trial with eicosapentaenoic acid was not effective for OCD (Fux et al. 1993a) and appear to . J. the reverse is also true. for 6 weeks. 1992b) and a desipramine controlled augmentation trial (Barr et some symptom improvement but no change in responder status (Ninan et al. 2004c). An open trial of venlafaxine in 39 patients. If patients do not have a good response to an adequate trial of at least two SSRIs. Thus. only 3 patients reported clinically significant improvement. higher dosages of 30–60 mg/day should be targeted. beginning with the most compelling ones. 2005a). satisfactory systematic comparisons of the various serotonin reuptake blockers. 2006). major depression: a considerable number of patients show a negligible or partial response to the first-line medications. Three meta-analytic studies have addressed these questions by retrospective analyses of treatment data from past trials. a 12-week placebo-controlled trial of St. 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. an extremely large prospective study would have to be undertaken in order to demonstrate small but significant differences between the various medications. John's wort monotherapy yielded negative results (Kobak et al. or fluvoxamine-treated (McDougle et al. 1992a). As these augmentation strategies are more rigorously tested. Evidence in support of MAOIs is very weak despite a positive report (Vallejo et al. Medication combination and augmentation It is important to keep in mind that the medication response in OCD is not as dramatic as in. 1991a). a meta-analysis of pediatric studies found superiority for clomipramine and comparable efficacy among SSRIs (Geller et al. 1993b) patients. 1993). 1997). possibly with the exception of some benefit for symmetry obsessions from phenelzine (Jenike et al. 2003). because in clinical practice actual or expected tolerability of different medications often takes precedence over small differences in efficacy. leaving inositol as an option of unclear efficacy (Seedat and Stein 1999). A controlled trial of lithium augmentation was also negative (McDougle et al. Although clomipramine appears to have an edge over SSRIs in treating OCD. 1995b. The SSRIs are better tolerated than clomipramine by most patients. As a helpful rule of thumb. because of clomipramine's strong anticholinergic side effects. McDougle et al. fluoxetine-treated (Grady et al. The SNRI venlafaxine also appears effective in treating OCD. Still. as were a trazodone controlled trial (Pigott et al. If tried. A controlled study of lithium augmentation of clomipramine did not detect any benefit (Pigott et al. 18 mg/day. Stein et al. Similarly. OCD patients with comorbid tic disorders may actually be less responsive to SSRI monotherapy (McDougle et al. A controlled study of trazodone alone in OCD again showed no benefit compared with placebo (Pigott et al. In the following discussion we summarize the findings in favor of or against the various augmenting agents for OCD. D. The clinical applicability of this finding may.

A small brief double-blind augmentation trial showed similar improvement in obsessions with risperidone and haloperidol compared with placebo (Li et al. duration of illness. and an episodic course of illness. higher frequency of compulsions. 2006).5 mg tid was significantly superior in reducing OCD symptoms (Dannon et al. 2005). Risperidone has been successfully used for augmentation in open trials. 1996). poorer insight into their OCD. 2005).respond well to haloperidol augmentation (McDougle et al. Denys et al. Another placebo-controlled risperidone augmentation trial using low-dosage risperidone in 45 patients also reported modest efficacy over placebo (Erzegovesi et al. with good results for horrific mental imagery rather than comorbid tic disorders (Saxena et al. and such a strategy is now supported by controlled trials. compared with placebo. Other somatic treatment options Although there are no definitive predictors of medication treatment response. borderline. 3 mg/day. In another 8-week open trial in which risperidone. 2004a). 2000). reported modest results. In one small randomized trial in patients with refractory OCD. 1998). other medications have been used for augmentation in those with treatment-resistant OCD. 2005). Nonresponders had more severe symptomatology. washing rituals. 2004). regarding atypical antipsychotic augmentation is that these agents have modest efficacy but are worth trying in patients with treatment-resistant illness. although reports are contradictory. whereas another reported significant improvement compared with placebo at a mean dosage of about 10 mg/day. age at onset. longer duration of illness. 2000). then. with 15% of patients discontinuing treatment due to side effects (Bystritsky et al. was added to an SSRI in 20 patients with refractory OCD. Preliminary data on the antiglutamatergic agent riluzole appear promising (Pittenger et al. The general conclusion. Beyond antipsychotics. More recently. 1999). sudden onset of OCD. 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. and this response was not associated with the presence of tics or schizotypy. Two placebo-controlled quetiapine augmentation studies yielded negative results (P. 2002. and the presence of avoidant. all subjects were described as showing some improvement (Pfanner et al. several factors appear to be predictive of a poorer prognosis. citalopram combined with clomipramine led to significantly greater improvement than citalopram alone (Pallanti et al. and comorbid eating disorder (Hollander et al. with 40% of patients rated as responders (Hollander et al. in dosages of 10–30 mg/day. Fineberg et al. D. pindolol at 2. . a chronic course. Fourteen patients with treatment-refractory OCD who had not responded to three SSRI trials received paroxetine augmentation with pindolol or placebo for 6 weeks. 2000). A case report of successful topiramate augmentation of paroxetine treatment has been reported (Hollander and Dell'Osso 2006). to their ongoing regimen (Coric et al. Carey et al. The combination of clomipramine with an SSRI is also a commonly used strategy for treating refractory patients and is generally well tolerated. Four pediatric patients with refractory OCD have also been described as responsive to risperidone augmentation (Fitzgerald et al. one placebo-controlled augmentation trial found no benefit (Shapira et al. Olanzapine has been reported beneficial in four open-label augmentation trials. Similarly. An open trial of bupropion monotherapy at 300 mg/day reported no benefit (Vulink et al. and schizotypal as well as multiple personality disorders. augmentation of fluvoxamine with the antiglutamatergic amino acid N-acetylcysteine was reported effective (Lafleur et al. about half of 13 patients with treatment-resistant OCD responded to the addition of riluzole. 2005). another study has supported the effectiveness of pulse-loaded intravenous clomipramine in treatment-resistant OCD (Koran et al. 2006). In more recent years. When oral medications fail to be successful enough in patients with highly refractory illness. 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. 2003a). prior hospitalizations. 50 mg bid. Intravenous clomipramine has met with some success in OCD refractory to oral clomipramine (Fallon et al. 2005). In an open trial. 2006). or symptom subtypes. 2005. including earlier onset. however. with some improvement in three of seven participants (Connor et al. In a single case report. 2005). 2004). other somatic treatment options can be considered. Responders had a higher incidence of family history of tics. Clozapine has been reported to worsen OCD. although lower dosages of clomipramine should be used with monitoring of blood levels to avoid toxicity because clomipramine levels can become markedly elevated. Another placebo-controlled risperidone augmentation trial similarly showed better results than placebo. 2006). A review of 274 OCD patients found no differences between responsive and nonresponsive subjects in age. regardless of comorbid tics or schizotypy. 1994). A small open monotherapy trial of aripiprazole. whereas two other placebo-controlled augmentation trials reported that approximately 50%–60% of patients responded to the augmentation (Atmaca et al. atypical antipsychotics have received increasing attention as a major augmentation strategy for OCD. 2001). 1999). gender.

Conversely. contraindications. At follow-up after several years. Recently. 1995c). 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. This response rate was confirmed in a 2-year prospective cingulotomy study (Baer et al. 1999).. is deep-brain stimulation (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. risks. and many patients may require indefinite drug treatment to stay well. although its efficacy is very debatable (Maletzky et al. and there were few adverse effects (Dougherty et al. 2001). 2000). Jenike et al. 1999). indications. A sham-controlled low-frequency TMS treatment of the right prefrontal cortex did not report significant benefit (Alonso et al. documented failed treatments. neurosurgery can be considered. In four highly refractory OCD patients.. 2005). In exposure therapy. benefits.g. and he or she may require assistance from the therapist (in a home visit) or from family members to achieve exposure at home. 1994). cingulotomy resulted in notable improvement. in a double-blind discontinuation study of OCD patients who had done well on clomipramine for about 1 year. an open pilot trial of low-frequency TMS delivered to the supplementary motor area reported benefits (Mantovani et al. 2001). 2003). most patients remained symptomatic and required continued pharmacotherapy. with a substantial minority of 20% remaining refractory to multiple treatment regimens (Leonard et al. Response prevention involves having patients face feared stimuli (e. Initial work may involve delaying performance of the ritual. 2006). including selection. 1995). but ultimately the patient works to fully resist the . Similarly. A review of 29 patients who underwent capsulotomy between 1976 and 1989 at the Karolinska Hospital in Stockholm. In a long-term blinded electrical capsular stimulation study. 2001). 2006). have been thoroughly reviewed elsewhere (Mindus and Jenike 1992). chemicals) without excessive hand washing or tolerate doubt (e. but plasma exchange treatment was found not to help children whose OCD did not have streptococcus-related exacerbations (Nicolson et al. and workup.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. "Is the door really locked?") without excessive checking. Similarly. Long-term continuation of medication treatment generally maintains a good treatment response. repetitive transcranial magnetic stimulation (TMS) has been used to treat OCD. A new development. this treatment resulted in dramatic improvement in one patient and moderate improvement in another (Abelson et al. Maintenance treatment OCD tends to be a chronic illness. In extreme cases of severely impaired patients with refractory OCD. Electroconvulsive therapy may be considered in highly refractory cases. the patient is assigned homework exercises that must be adhered to. In a thorough retrospective analysis. which if successful may gradually replace neurosurgery for refractory OCD. 1993). 2002). three of four patients with refractory illness responded to the treatment (Nuttin et al. 1997). Exposure techniques range from systematic desensitization with brief imaginal exposure to flooding.g. 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. Higher cerebral metabolic activity in the posterior cingulate presurgery has been identified as a predictor of better response to cingulotomy (Rauch et al. 90% had substantial worsening within 7 weeks (Pato et al. 2001). Sweden. 1991) estimated that in at least 25%–30% of patients. 1988). during which they maintained or even slightly improved their gains (Rasmussen et al. Exposure techniques aim to ultimately decrease the discomfort associated with the eliciting stimuli through habituation. In a subsequent study. 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. although the absence of a sham control group makes interpretation of efficacy difficult (Sachdev et al. dirt. found that positive clinical outcome was associated with lesioning to the middle of the right anterior limb of the internal capsule (Lippitz et al. in which prolonged exposure to the real-life ritual-evoking stimuli causes profound discomfort. 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. Guidelines for the use of neurosurgical techniques in the treatment of severe refractory OCD. 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.

Foa et al. clomipramine alone. The psychoeducation and support of family members can be pivotal to the success of the behavioral therapy. and overall impairment. Similarly in children. suggested that behavior therapy may have an edge over medication therapy (Foa et al. their combination. a study comparing behavioral treatment versus clomipramine found that both were similarly helpful. longer duration. whereas for full remission the two approaches had a similar effectiveness of about 25% (Fisher and Wells 2005). however. and illogical inferences.compulsions. up to 75% of ritualizing patients willing and able to undergo the arduous treatment were reported to show significant improvement (Marks et al. possibly as a way to reduce the anxiety or anger that patients may direct at their family members. excessive responsibility. TABLE 12–28. 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). although new behavioral techniques for obsessions may also be promising. 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%. suggesting that. Similarly. estimation of catastrophe. 1994). exposure and response prevention (ERP)—yield the greatest improvement. initial OCD severity. defined as those patients who showed at least 30% improvement with treatment. 2005). 42%. 55% for exposure. ERP has also been used successfully to treat children and adolescents with OCD. Of interest. 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. 2001. 1975). patients who were treated with ERP relapsed significantly less than those treated with medication alone (Simpson et al. McKay 1997). and 90% for ERP. 2004). It is also generally reported that patients who primarily experience obsessions and have few rituals are the least responsive to behavioral treatment. SSRIs. 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. respectively). 1998). 70%. 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). The study compared ERP alone. this study found that the majority of OCD patients successfully treated with behavior therapy had relapsed at follow-up. van Oppen et al. expectations about anxiety and its consequences. A maintenance program can be highly effective in helping patients maintain their benefits from CBT over several years of follow-up (Marks 1997. 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. long-term behavioral maintenance treatment may be necessary. just as with medication. ERP alone. A meta-analytic comparison study of OCD treatments. and the two treatments combined (ERP). 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. 2005b. because family dysfunction is very prevalent and the majority of parents or spouses accommodate to or are involved in the patients' rituals. Whittal et al. Cognitive therapy has also been more recently advocated and is efficacious in the treatment of OCD. Using the combined techniques of in vivo ERP. Several studies have directly compared cognitive versus behavioral therapy for OCD in randomized trials and have reported similar efficacy (Cottraux et al. with at least 50% improvement in the vast majority of participants (Franklin et al. response prevention. Predictors of poorer outcome for behavioral treatment of OCD include initial depression. and lower motivation for treatment (Keijsers et al. 2005). A recent 12-week multicenter study. ERP and combination treatment had a greater edge over clomipramine alone for remission compared with response. (1984) systematically compared in vivo exposure. or . All groups improved. and 8%. was 33% for response prevention. The proportion of clinical responders. 1998). a sizable number of patients did not achieve remission by the end of treatment regardless of the type of treatment. but the combined treatment was superior in decreasing anxiety. 1995. after controlling for a number of confounding variables. and ERP all had comparable results (Kobak et al. found that clomipramine. centering on cognitive reformulation of themes related to the perception of danger. rituals. thought–action fusion. Simpson et al. There is also evidence that in the short term (12 weeks) after treatment discontinuation. 1998).

OCD patients need supportive treatment even while pharmacotherapy or behavior therapy is being applied. illusions. POSTTRAUMATIC STRESS DISORDER Definition PTSD was first introduced in DSM-III. or a threat to the physical integrity of self or others (2) the person's response involved intense fear. OCD has generally proven refractory to psychoanalytically oriented as well as to loosely structured. spurred in part by the increasing recognition of posttraumatic conditions in veterans of the Vietnam War. Note: In young children. including images. and most maintained it at 6-month follow-up. DSM-IV-TR diagnostic criteria for posttraumatic stress disorder A.psychotherapy combined with medication. trauma-specific reenactment may occur. procrastination. The person has been exposed to a traumatic event in which both of the following were present: (1) the person experienced. there may be frightening dreams without recognizable content. 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. repetitive play may occur in which themes or aspects of the trauma are expressed. especially by psychiatrists. poor insight and low CBT effort predicted lesser gains (Tolin et al. hallucinations. B. A common approach used in clinical practice. 1999). in a wait-list controlled trial of CBT in OCD patients who had failed to adequately respond to multiple serotonin reuptake inhibitor medications. is to start out with medication. Other Psychotherapy Patients with OCD frequently present with symptoms that appear laden with unconscious symbolism and dynamic meaning. medication and CBT are approximately equal first-line treatment choices. In a study testing this commonly used paradigm. in sum. patients initially treated with medication were more likely to be taking medication at follow-up (van Oppen et al. nondirective. The traumatic event is persistently reexperienced in one (or more) of the following ways: (1) recurrent and intrusive distressing recollections of the event. and dissociative flashback episodes. Despite the similar efficacy of pharmacotherapy and CBT for OCD. this may be expressed instead by disorganized or agitated behavior. (2) recurrent distressing dreams of the event. In brief. is commonly used and recommended in the treatment of OCD. (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 . The current DSM-IV-TR diagnostic criteria for PTSD are presented in Table 12–29. Similarly. it appeared quite effective. doubting. about 50% showed clinically significant improvement. either concurrent or sequential. the latter group showed significantly greater benefits (Tenneij et al. 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. attain a degree of clinical improvement that will allow better utilization of CBT. and then possibly attempt some degree of medication taper once CBT has been mastered and effective. and indecisiveness (Salzman 1985). regardless of degree of initial response. given the common failure of either treatment to achieve a strong enough response or remission. 2004). So. TABLE 12–29. these patients may require a great deal of reassurance during the early phase of treatment. In contrast to its lack of efficacy in treating chronic OCD. 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. Because of their tendency toward excessive doubt. thoughts. In another study. More active supportive therapy that encourages risk taking helps OCD patients live with their anxiety. the conclusion is that patients who are initially treated with medication. Note: In young children. Note: In children. combination therapy. including those that occur on awakening or when intoxicated). or horror. helplessness. 2005). However. or was confronted with an event or events that involved actual or threatened death or serious injury. exploratory psychotherapies. and a focus on the present has been reported to be helpful (Salzman 1985). 2005). (3) acting or feeling as if the traumatic event were recurring (includes a sense of reliving the experience. with an overall remission rate of about 50%. have a good likelihood of some further improvement with the introduction of CBT. Note: In children. witnessed. or perceptions.

or conversations associated with the trauma (2) efforts to avoid activities. and D) is more than 1 month. interpersonal relationships. and hyperarousal have been maintained. Persistent symptoms of increased arousal (not present before the trauma). or a normal life span) D. 82% of those who met acute stress disorder criteria were diagnosed with PTSD 6 months later (Bryant and Harvey 1998). classifies all such disorders as stress related. and conversion symptoms. It has now been well established by a number of studies. C. 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. feelings. as opposed to only 11% of those without acute stress. In acknowledgment of the spectrum of disorders stemming from severe stress." Increasing attention has been drawn in recent years to the concept of "trauma-spectrum" disorders. DSM-IV added acute stress disorder to the anxiety disorders. whereas they are not addressed in the PTSD description. acute stress disorder.g. Duration of the disturbance (symptoms in criteria B. does not expect to have a career.. somatoform. children. marriage. as indicated by three (or more) of the following: (1) efforts to avoid thoughts. occupational. Investigators such as Herman and van der Kolk (1987) had originally suggested that a discrete entity of complicated posttraumatic syndromes be recognized.g. The disturbance causes clinically significant distress or impairment in social. dissociative symptoms figure prominently in the definition of acute stress disorder. 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. Not all investigators agree that PTSD belongs with the anxiety disorders. and a steady 80% were diagnosed with PTSD 2 years after the accident (Harvey and Bryant 2000). In a study of people who had mild traumatic brain injury in motor vehicle accidents. or other important areas of functioning. characterized by lasting changes in identity. 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. emotional numbing. which can include admixtures of posttraumatic stress. and the sense of life's meaning (Herman et al.C.. otherwise designated as "DESNOS" (disorders of extreme stress not otherwise specified). it may well be that the two should not be defined as discrete disorders. ICD-10 (World Health Organization 1992). In addition. that acute stress disorder is a highly reliable predictor of developing PTSD down the road. dissociative. Acute stress disorder is similar to PTSD in the precipitating traumatic event and in symptomatology. unable to have loving feelings) (7) sense of a foreshortened future (e. subdividing the disorder into acute or chronic. the disorder is classified with the anxiety disorders. and the major criteria of an extreme precipitating stressor. and the classification approach to trauma-related conditions is a subject of ongoing debate. pathological bereavement. Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (not present before the trauma). places. Similar personality changes are recognized by the ICD-10 and classified as "enduring personality change after catastrophic experience. so are depression and dissociation. New duration criteria were also established. for example. including prospective ones. Although anxiety is a prominent symptom. van der Kolk and Saporta 1991). 1989. 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. increasing attention has been drawn to an enduring constellation of traits that frequently develop in individuals subjected to chronic trauma as children or adults. and adjustment disorders. . up to 1 month after the event. F. intrusive recollections. 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. Beyond the symptoms of PTSD per se. but it is time limited.

guilt about not having prevented the traumatic experience. the lifetime prevalence of PTSD was similarly found to be 7. hostile behavior. B. too few in number to meet the full diagnostic criteria. Such individuals. The comorbidity of PTSD with depression is a very consistent one. panic. The most common stressors were combat exposure in men and sexual assault in women (Kessler et al. unreal state with hazy memory and a distorted sense of time. Dissociative states may occur. self-injurious behavior and suicide attempts. The Australian National Survey of Mental Health and Well-Being. Epidemiological analyses suggest that in trauma victims the vulnerabilities for PTSD and depression are not separate.7% of women and 1. In a Canadian community survey. 1991). On the other hand. A woman is raped and severely beaten by an unknown assailant. panic attacks. seemingly women in particular. reexperiencing of the trauma. the lifetime prevalence of PTSD was found to be 9. a prospective study of a large sample of trauma survivors found depression and PTSD to be independent sequelae of trauma (Shalev et al.3% of men. The prevalence was higher in women (11. it is clear that PTSD in women increases the risk for new onset of both depression and alcohol use disorder (Breslau et al. Epidemiology Although there are marked individual differences in how people react to stress. has been consistent across a number of studies. and interference with interpersonal relationships. 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.3%) than in men (6%). full PTSD was found in 2. 2000). difficulty concentrating. Other accompanying or complicating symptoms associated with PTSD may include substance abuse.000 participants. It appears that women are more likely to develop PTSD than men with comparable exposure to traumatic events. with feelings of being detached from other people. shame. the rate of morbidity rapidly increases. 1997).4% of women and 0. Psychic numbing or emotional anesthesia is manifest by diminished responsiveness to the external world. Rape or mugging victims sometimes become afraid to venture forth alone for variable periods of time. whereas partial PTSD was found in an additional 3. which is usually less severe and within the range of common life experience. Symptoms of excessive autonomic arousal may include hyperactivity and irritability. depression. are quite common in the general population. 2006). when stressors become extreme. loss of interest in usual activities. increased irritability. Situations reminiscent of the original trauma may be systematically avoided. especially if exposure is before age 15 (Breslau et al. 1997a). In the National Comorbidity Survey. such as in concentration camp situations or in extended combat. Individuals with PTSD may be more likely to manifest borderline or self-defeating personality disorder. This difference is not well understood and could involve characteristics of both the individuals and the traumatic experiences. For example. of about 10. Symptoms of PTSD.Clinical Description A soldier participates in the torture and murder of civilians.2% of men. and depression. The characteristic features that may develop after traumatic events such as these include psychic numbing. and it appears that the actual PTSD diagnosis rather than the trauma history accounts for this association (Shea et al. 1995). this relationship between the severity of the stressor and the type of subsequent symptomatology is not always predictable. The gender difference in PTSD prevalence. lasting from minutes to days. an exaggerated startle response. a high comorbidity risk was found for OCD. In a large randomized community survey of young adults. However. A high rate of comorbid disorders is found in PTSD. 1980). and impulsive behavior. and increased autonomic arousal. and rage.2% (Breslau et al. 1998b). occupational impairment. 2000). There may be prolonged episodes of intense affect. or nightmares. explosive. and sleep abnormalities. 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. In the Breslau et al. Stein et al. or sexual interest. anxiety. higher in women. 1998a. tenderness. Regardless of causality.8% and was again more common in women. in which there is a dreamlike. Other symptoms may include guilt about having survived. The trauma is reexperienced in recurrent painful and intrusive recollections. A passenger is the sole survivor of a commercial airliner. In effect. and inability to feel emotions such as intimacy. 1997b). agoraphobia. daydreams. it has generally been underestimated that in . may be important to identify because they experience clinically meaningful distress and functional impairment (M. Etiology The severity of the stressor in PTSD differs in magnitude from that found in adjustment disorder. (1991) survey. whereas the association with drug or alcohol abuse was weaker. but rather the risk for depression is highly elevated in just those trauma victims who manifest PTSD (Breslau et al. and the nature of the relationship between the two conditions is controversial.

In addition. Although the disorder can certainly develop in people without significant preexisting psychopathology. 1991). events such as sexual assault or armed robbery. previous adversity has been associated with a higher likelihood of developing PTSD.the average community setting. 2000). different risk factors for becoming exposed to . extremely high PTSD incidences of 84% lifetime and 59% decades after have been reported (Engdahl et al. those with PTSD had higher rates of childhood physical abuse than those without PTSD. rape. with experiencing physical abuse or witnessing domestic violence being the strongest contributors (Silva et al. In addition. torture. An epidemiological survey identified. 1993b). Variable rates have been found in individuals subjected to major noninterpersonal trauma such as in severely injured accident victims. are particularly likely to lead to PTSD. Still. and security. 2001) to 32% (Koren et al. a number of biological and psychological variables have been identified that render individuals more vulnerable to the development of PTSD. the ECA study found that in men who had served in Vietnam. however. more than half of the traumatized children had syndromal or subsyndromal PTSD. In an inner-city child psychiatry clinic. Nevertheless. as is widely known clinically and documented by numerous studies. 1997).. 1980). the rate of morbidity significantly increases. whereas preexisting psychological disorders better predicted the persistence of posttraumatic symptoms over time. as described by McFarlane (1990). a definite dose–response relationship exists between the impact of the trauma and PTSD. or neglect had PTSD (Widom 1999). 1999). and good adolescent relationships who experienced prolonged trauma in Vietnam and developed severe PTSD (Lindy et al. In a large community sample followed prospectively into young adulthood. As an average. this study reported a number of patients with good premorbid adjustment. extended combat. self-esteem. low childhood trauma. Childhood interpersonal trauma can often result in PTSD. In a study of Vietnam veterans. When stressors become extreme (e. common events such as sudden loss of a spouse are a much more frequent cause for PTSD than assault and violence (Breslau et al. In general. In even more horrendous conditions. In one study of a Vietnam veteran outreach center. 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. After severe traumatic brain injury.g. it is estimated that approximately one-fourth of all individuals who experience major trauma develop PTSD (Breslau et al. McFarlane (1989) found that the severity of exposure to disaster was the major determinant of early posttraumatic morbidity. individuals with prior traumatic experiences are more likely to become exposed to future traumas. it is rare even for overwhelming trauma to lead to PTSD in more than half of the exposed populations. Risk Factors and Predictors There is agreement that a variety of premorbid risk factors predispose to the development of PTSD (Table 12–30). a prior history of good adolescent friendships was predictive of PTSD. 1984). For example. the more likely he or she is to develop symptoms after a stressful life event (Horowitz et al. or concentration camp experiences). clearly suggesting that other etiological factors also play a role (McFarlane 1990). whereas 20% of those in combat who had been wounded developed PTSD. whereas a history of poor adolescent friendships was more likely in those who did not have PTSD. a 27% PTSD incidence has been reported (Bryant et al. ranging from a very low 2% (Schnyder et al. In addition. about one-third of the children who had experienced substantiated sexual abuse. physical abuse. 4% of those who were in combat but were not wounded had PTSD. albeit retrospectively. as well as a significantly higher rate of total traumatic events prior to joining the military (Bremner et al. 1998). because they can be prone to behaviorally reenact the original trauma (van der Kolk 1989). TABLE 12–30. which are interpersonal insults to integrity. such as those experienced by American prisoners of war held by the Japanese during World War II. A discussion of such predictors follows. 2000).

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. Cognitive and Behavioral Theories A cognitive model has been proposed for the persistence of PTSD symptoms. 2000). 2004). Interestingly. 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. 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. 2000). 2006). Other findings of great interest are that the administration of certain agents medically indicated in the acute aftermath of medical traumas (e. 1999). depression. shortly after trauma is a significant predictor of later PTSD (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). 1996). suggesting that PTSD becomes persistent when individuals process the trauma in a way that leads to a sense of serious and current threat. As previously stated. the occurrence of acute stress disorder in the first month after trauma is a very strong predictor of later PTSD.g. having been sensitized by stress (Grillon and Morgan 1999). 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. 1999). One prospective study has also implicated lower plasma GABA levels peritraumatically in the development of later PTSD (Vaiva et al. Neurological compromise. Early predictors of PTSD after a traumatic event have also received great attention. 2000). and family history of anxiety. because of their obvious potential significance for early intervention and prevention. is also associated with PTSD (Gurvits et al. Shalev et al.trauma and for developing PTSD after traumatic exposure (Breslau et al. with larger responses to unpaired cues and reduced extinction of conditioned responses (Peri et al. even in the absence of elevated trauma (Yehuda et al. extraversion. high heart rate and decreased cortisol in the acute aftermath strongly correlate with later PTSD (Yehuda et al. In a prospective study. Although peritraumatic dissociation may serve as one "marker" helpful in identifying individuals at high risk for developing PTSD. 1998). 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). Also. 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. 1991). 2004). 2003). 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. childhood conduct problems. cardiac surgery. intensive care unit stays. . known as peritraumatic dissociation. 2005). with modest specificity and sensitivity (Zatzick et al. 2000). on its own. burns) may be protective against developing later PTSD. 2004). Individuals with PTSD also generalize fear-related conditioned responses across stimuli. 1998a). 1994. Risk factors for developing PTSD after traumatic exposure were disrupted parental attachments. and family history of substance abuse or psychiatric problems. 2001).. is a strong predictor of the later development of PTSD (Marmar et al. so peritraumatic dissociation should be viewed as one predictor in the context of other factors in the aftermath of trauma (Ozer et al. Risk factors for exposure to trauma were male sex. Autonomic responses to both innocuous and aversive stimuli are elevated. Findings with regard to gender are conflicting. anxiety. Having a past history of PTSD increases the risk for both acute and chronic PTSD (Ursano et al. Even elevated heart rate. parental PTSD is also a risk factor for PTSD in offspring. 1998b). Compared with nonchronic PTSD. 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. 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. For example. 2005). Behavioral theory suggests that there is a disturbance of conditioned responses in PTSD. 1998b). 1999). An additional risk factor that has been associated with higher likelihood of developing PTSD is lower premorbid intelligence (Macklin et al. Having an Axis II disorder also increases the risk for chronic PTSD (Ursano et al. many individuals go on to develop PTSD in the absence of pronounced peritraumatic dissociation. Similarly. Increased attention to dissociative phenomena and their relationship to posttraumatic symptoms has revealed that greater dissociation around the time of the traumatic event. with increased neurological soft signs and childhood histories of neurodevelopmental problems and lower intelligence. 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.

cingulate) and cortical hyporesponsivity (prefrontal. with subsequent depletion of central norepinephrine (Anisman et al. Biological theories related to trauma are listed in Table 12–31. suggesting that avoiding the encoding of disturbing information does not occur in PTSD (McNally et al. Animals that have experienced previous inescapable shock are more sensitive to norepinephrine depletion. Broca's area) to traumatic stimuli Hypothalamic-pituitary-adrenal axis dysregulation Noradrenergic activation Heightened physiological responses Endogenous opioid dysregulation Dysregulated serotonergic modulation Hippocampal toxicity. Long-standing increases in the urinary catecholamines norepinephrine and epinephrine have been found in PTSD patients. 1987). 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. 1995). Biological models of posttraumatic stress disorder Limbic hyperactivity (amygdala. 2005). originating in the locus coeruleus. possibly as a consequence of chronic noradrenergic hyperactivity. 1980). 2004b). In an epidemiological community study. In addition. This manifests itself in the "positive" symptoms of PTSD—that is. identifying five cardinal features: 1) persistence of startle response. A decrease in the number and sensitivity of 2-adrenergic receptors. and 5) overall constriction of the personality." implying an interaction of psychological and biological processes. as well as elevated plasma norepinephrine (Spivak et al.Recent studies have also revealed a number of disturbances in cognitive processes associated with PTSD. A wide range of data supports this hypothesis. For example. Elevated CSF norepinephrine has also been identified in men with chronic PTSD compared with control subjects (Geracioti et al. Impairments in explicit memory have been associated with PTSD (Bremner et al. 1987) and yohimbine (Southwick et al. Janet described the breakdown in normal adaptation. respiration. He labeled this condition as a "physioneurosis. The noradrenergic system. 1998). Biological Theories More than a century ago. such as lactate (Rainey et al. heightened physiological responses to stressful stimuli such as blood pressure. Pitman et al. Kardiner (1959) comprehensively described the phenomenology of war traumatic neurosis. 3) atypical dream life. Studies of the startle response in PTSD have reported heightened amplitude of startle in some samples but not in others (Lipschitz et al. heart rate. which serves as a forerunner of current psychobiological models of PTSD. 2000). 1999). regulates arousal. Pavlov (1927/1960) demonstrated chronic change in autonomic nervous system activity level in response to repeated traumatic exposure. Agents that stimulate the arousal system. information processing. induce flashbacks and increases in core PTSD symptoms. 2004). 1997). and electromyographic activity have long been documented (Kolb 1987. 4) explosive outbursts. 2001). 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. Endogenous Opioid System . Freud (1919/1955) implicated a biological basis to posttraumatic symptoms in the form of a physical fixation to the trauma. the hyperarousal and intrusive recollections. When PTSD develops under severe or repeated trauma. 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. In patients with PTSD. galvanic skin responses. 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). PTSD was associated with significantly elevated urinary catecholamine levels (Young and Breslau 2004a. 1993a) and may be related to hippocampal toxicity resulting from stress-mediated elevations in norepinephrine (Bremner et al. has been reported (Perry et al. 2) fixation on the trauma. and chronic autonomic hyperactivity sets in. These releases include heightened secretion of catecholamines and cortisol. This appears consistent with the intrusive nature of traumatic memories clinically encountered in the disorder. 1987). PTSD subjects may not exhibit recall deficits for trauma-related words but rather for positive and neutral words. Animals exposed to inescapable shock initially show evidence of increased turnover of norepinephrine. TABLE 12–31. the stress response becomes dysregulated.

The septohippocampal brain system contains serotonergic pathways and mediates behavioral inhibition and constraint. this appears to be a separate subgroup of PTSD subjects from the ones exhibiting noradrenergic sensitization (Southwick et al. 2005). 1999). 1997a). 1997). Pitman et al. Neuropeptides One study found significantly elevated basal CSF substance P in PTSD patients compared with control subjects. The efficacy of SSRIs in PTSD is also indirectly supportive of dysregulated serotonergic modulation in PTSD. This withdrawal may then contribute to the hyperarousal symptoms of PTSD. The partial serotonin agonist m-CPP induces an increase in PTSD symptoms suggestive of a sensitized serotonergic system. The noradrenergic and opiatergic systems of the brain interact and may serve reciprocal functions. which appears to be mediated by release of endogenous opiates and is blocked by the opiate antagonist naloxone (Maier et al. 1984). 1980). opiate withdrawal may set in. and positive coping (Yehuda et al. 2005). clinical and community samples have revealed absence of lower basal concentration or enhanced suppression of cortisol (Lindley et al. Van der Kolk et al. enhanced suppression of cortisol after dexamethasone administration. the irritability and outbursts seen in patients with PTSD may be related to serotonergic deficit. PTSD patients. (1990) compared pain intensity with thermal stimuli in Vietnam veterans with PTSD and veterans without PTSD who were watching a war videotape. and decline in functioning associated with PTSD. Animals prevented from escaping from severe stress develop a syndrome of learned helplessness (Maier and Seligman 1976) that resembles the symptoms of constricted affect. 1986) and an elevated urinary norepinephrine/cortisol ratio (Mason et al. Animals exposed to prolonged or repeated inescapable stress develop analgesia. The role of serotonergic deficit in impulsive aggression has been studied extensively. leading the individual to a vicious cycle of traumatic reexposures in order to gain transient symptomatic relief. 2006). The findings include elevated CSF corticotropin-releasing hormone (Bremner et al. 2006). it is suggested that in humans who have sustained prolonged or repeated trauma. there was a marked increase in CSF substance P (Geracioti et al. and normal urinary cortisol levels (Young and Breslau 2004a). (1984) proposed that animal models of inescapable shock may parallel the development of PTSD in humans. a blunted adrenocorticotropic hormone response to CRF (Smith et al. low urinary cortisol (Mason et al. A PET study of 5-HT1A receptor binding found no change in PTSD (Bonne et al. 2005). this analgesia was eliminated with naloxone pretreatment. For example. recent research has suggested a biological component to the "negative" symptoms of PTSD. and under traumatic symptom provocation. Serotonergic System The serotonergic system has also been implicated in the symptomatology of PTSD (van der Kolk and Saporta 1991).Although in the past affective numbing was understood primarily as a psychological defense against overwhelming emotional pain. 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. 1989). leading to analgesia and psychic numbing (van der Kolk et al. After a transient opioid burst upon reexposure to traumatic stimuli. withdrawal. In animals. Brain Neuroanatomy and Neurocircuitry Structural neuroimaging findings in PTSD have generally reported smaller volumes in brain structures involved in the . and interestingly. lower combat exposure. but not control subjects. normal peripheral and elevated CSF cortisol levels (Baker et al. had a 30% analgesia when pretreated with a placebo injection. amotivation. although such work is still in its infancy. normal ambient salivary cortisol levels (Young and Breslau 2004b). not all studies of the HPA axis in PTSD are consistent with this profile. A blunted prolactin response to fenfluramine challenge is supportive of central serotonergic dysregulation in PTSD (Davis et al. and decrease in lymphocyte glucocorticoid receptor number. Similarly. However. Another study found that neuropeptide Y plasma concentrations were associated with degree of symptom improvement. On the basis of such findings. Thus. 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. the concept of trauma addiction has been proposed (van der Kolk et al. but not after neutral provocation. 1984). 1995). 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. repeated inescapable shock can lead to serotonin depletion. accompanied by a subjective sense of calm and control. 1988). endogenous opiates are readily released with any stimulus that is reminiscent of the original trauma.

In contrast to the relative deactivation of prefrontal and cingulate regions in PTSD reported in response to threatening stimuli.modulation of emotion and memory. and visual association cortex (Bremner et al. whereas no etiological role was found for shared environment (True et al. absence of ventromedial prefrontal cortex deactivation in traumatized non-PTSD control subjects may be a compensatory. To further complicate matters. in a total of 133 patients. indicative of a generalized hypervigilance (Bryant 2005). what the developmental determinants are. 2005). 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. it remains unclear to what degree smaller hippocampi constitute a preexisting vulnerability to PTSD. 2004). and visuospatial processing (Bremner et al. PET imaging during auditory exposure to traumatic scripts has shown that abuse memories are associated with decreased blood flow in the medial prefrontal cortex. smaller hippocampi have been found in monozygotic twins of veterans with PTSD who were not exposed to combat. 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. 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. 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. to name a few. Furthermore. 2006). 2004). The exaggerated amygdalar response to emotional stimuli has also been found to be present early in the course of acute PTSD (Armony et al. has been reported in several PTSD studies. with numerous studies reporting decreased hippocampal volume in adults with PTSD. as well as to traumatic stimuli. emotion. 1996). Furthermore. 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. not replicated later (J. 1999). 2006a). including combat veterans (Bremner et al. controlling for total brain volume. Gelernter et al. Exposure of PTSD subjects to traumatic stimuli results in decreased blood flow in the medial prefrontal cortex. 2005). an area responsible for the regulation of emotional response via inhibition of the amygdala (Bremner et al. Smaller hippocampi have also been found in comparable groups exposed to the extreme stress of large burns. 2006a. and this amygdala hyperactivation is dissociated from higher cortical inhibitory influences as evidenced by diminished medial prefrontal cortical activation (Phan et al. The animal literature does show that antidepressants promote hippocampal neurogenesis. When mental images of combat-related pictures are generated by PTSD veterans. An initial study found an association to a polymorphism of the dopamine D2 receptor (Comings et al. blood flow increases in the amygdala and anterior cingulate and decreases in Broca's area. then. 1999). Similar to mood and other anxiety disorders. 2005). anterior cingulate responses to nonthreatening stimuli may be enhanced. In adult patients with PTSD. However. 1997). Course and Prognosis . compared with matched non-PTSD control subjects (Tupler and DeBellis 2006). 1993). Decreased anterior cingulate volume has also been reported in PTSD. 1995). regardless of PTSD presence (Winter and Irle 2004). hippocampus. 2000. found decreased right and left volumes compared with traumatized and nontraumatized control subjects (Kitayama et al. 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. adult survivors of childhood abuse (Bremner et al. or if smaller hippocampi are an outcome of traumatic stress or PTSD illness itself or its chronicity. Shin et al. 1999). Imaging studies before and after treatment in PTSD are not many. At this point. J. Rauch et al. On the other hand. but some compelling findings are emerging. 2004. The most consistent findings relate to the hippocampus. Molecular genetic studies of PTSD are very few. consistent with the general model of diminished ventromedial cortical inhibition (Woodward et al. These patterns may relate to the nonverbal emotional visual imagery involved in reexperiencing PTSD symptoms (Shin et al. Vermetten et al. the short allele genotype of the serotonin transporter gene has been preliminarily implicated in PTSD (H. 1999). 1996). with specific dysfunction in brain areas involved in memory. Enhanced amygdala activation to general negative stimuli. and police officers (Lindauer et al. A meta-analysis of nine studies that examined hippocampal volume in PTSD. Deficits in verbal memory have been correlated with decreased hippocampal volume in some (Bremner et al. Lee et al. 1997b). 2003). as well as a relationship of PTSD symptom severity to amygdala overactivation and prefrontal cortex hypoactivation (Shin et al. 2005). 2005). which enhances the ability to differentiate real threat (Levin et al. 1999). a reciprocal relationship has been shown between prefrontal cortex and amygdalar activation. 1995) but not all PTSD studies. one large study in children with PTSD found larger hippocampi.

symptoms of increased autonomic arousal. If symptoms persist beyond 4–6 weeks. and an obsessive preoccupation with it following the trauma. 1997). Phobic avoidance. with arousal and stimulation of the autonomic nervous system. Predisposed persons have higher levels of anxiety and dissociation at baseline. Even when correcting for comorbid psychiatric or medical disorders. 1999). Differential Diagnosis The differential diagnosis of PTSD is described in Table 12–33. highlighting the frequent chronicity of the illness. 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. and somatic symptoms may occur. and experiencing new traumatic events during the interim period. . and avoidance or reexperiencing of the traumatic event. and despondency. followed by symptoms of intense anxiety lasting at least 1 month. startle responses. 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. The patient's emphasis changes from preoccupation with the actual trauma to preoccupation with the physical disability resulting from the trauma. unemployment. Somatic symptoms. TABLE 12–32. The patient's life becomes centered around the trauma. poor physical health.The course and prognosis of PTSD are summarized in Table 12–32. Factors associated with a more chronic course were comorbid anxiety and somatoform disorders. In Stage III. and social functioning. depressive. history of alcohol abuse and childhood trauma were associated with less remission (Zlotnick et al. In another study. and angry outbursts may occur. as are substance abuse. However. or acute PTSD. Stage I involves the response to trauma. somatic. numbing of responsiveness. with subsequent changes in lifestyle. 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. the full remission rate from chronic PTSD over a 5-year prospectively studied period was only 18%. and behavioral symptoms for which the relationship between their onset and the traumatic event is less clear-cut may easily lead to misdiagnosis. the patient enters Stage II. demoralization. with disability. It is important to be aware that PTSD can often be a very chronic condition. chronic PTSD develops. Some patients may focus on compensation and lawsuits. 2005). chronic anxiety. and depression are common complications at this time. greater avoidant symptoms at baseline. personality. Feelings of helplessness and loss of control. an exaggerated response to the trauma. a wide variety of anxiety. Nonsusceptible persons may experience an adrenergic surge of symptoms immediately after the trauma but do not dwell on the incident. and unemployment. reliving of the trauma. and diminished well-being. disturbed family relations. it is therefore crucial in multiply afflicted patients to specifically identify and target PTSD (Zatzick et al.

but the nature of the precipitant and the symptom cluster of PTSD distinguish this condition from simple phobia. but if of sufficient severity. or situations that remind them of the trauma itself. sleep disturbance. caffeine. it must be treated aggressively.TABLE 12–33. including medical records and witnesses' observations. Mild concussions may leave no immediate apparent neurological signs but may have residual long-term effects on mood and concentration. However. fatigue. In some veteran outreach populations. delirium. patients may be aversively conditioned to the surroundings of the trauma and develop a phobia of objects. In addition. Phobic symptoms. when it occurs. Generalized anxiety disorder The symptoms of GAD. In PTSD. surroundings. laboratory examinations. is essential in a diagnostic workup. concern with physical health. Phobic disorders Following a traumatic event. whereas avoidance is accompanied by anxiety reduction that reinforces the avoidant behavior. emotional lability. are also present in PTSD. Symptoms such as psychic numbing. each concomitant disorder should be diagnosed. organic hallucinosis. A careful evaluation of the nature of the head trauma. or concussion. and vigilance and scanning. Malnutrition may occur during prolonged stressful periods and may also lead to organic brain syndromes. neurological examination. autonomic hyperactivity. and pessimistic outlook may occur in both disorders. because this diagnosis has important treatment implications. 70%–80% of patients meet diagnostic criteria for both disorders. the additional diagnosis of dysthymic disorder should be made. In this case. whereas PTSD has an acute onset often followed by a chronic course. Differential diagnosis of posttraumatic stress disorder (PTSD) Depression after trauma (numbing and avoidance may be present. Organic mental disorders that could mimic PTSD include organic personality syndrome. are often present in PTSD. Phobic patients experience anxiety in the feared situation. and vertigo. If major depression develops secondary to PTSD. irritability. or tobacco and thus may present with a combination of organic and psychological factors. depression. or organic intoxication and withdrawal states. both disorders should be diagnosed. patients with PTSD may cope through excessive use of alcohol. difficulty concentrating. DSM-IV-TR does not allow for the diagnosis of GAD if PTSD is present. the onset and course of the illness differ: GAD has an insidious or gradual onset and a course that fluctuates with environmental stressors. and. Other causes of organic mental disorder may occasionally mimic PTSD if anxiety. Survivors of death camps may have symptoms of an organic mental disorder such as failing memory. if indicated. followed by mental status evaluation. headaches. anhedonia. an organic mental disorder must be ruled out. apprehensive expectation. . amnestic syndrome. drugs. 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. altered sensorium or level of consciousness. Major depression is a frequent complication of PTSD. such as motor tension. memory. anger. head trauma. which are absent in GAD. or abnormal behaviors are present. Mood and Anxiety Disorders Major depression There is much overlap between PTSD and major mood disorders. the phobia may be symptomatically similar to specific phobia. impairments in family and social relationships. Dysthymic symptoms are frequently secondary to PTSD. personality changes. because comorbidity carries an increased risk of suicide. or focal neurological signs would suggest an organic mental disorder. Abnormalities of cognition.

Food and Drug Administration–approved.S. If symptoms are of sufficient severity to meet other Axis I criteria. and chaotic lifestyle. Depression and lethargy are the affective symptoms that occur most commonly. large controlled trials Other SSRIs: similar efficacy Venlafaxine. additional treatment of specific PTSD symptoms or comorbid disorders. Adjustment disorder Adjustment disorders are maladaptive reactions to identifiable psychosocial pressures. TABLE 12–34. Munchausen's syndrome) involves frequent doctor visits and surgical interventions. mirtazapine Other antidepressants Tricyclic antidepressants: overall modest results when tested in double-blind fashion Monoamine oxidase inhibitors: may be superior to tricyclics. well-tolerated. Postconcussion syndrome Mental disorders secondary to head injury are influenced by physiological. such as reexperiencing the trauma. Sertraline: U. The prognosis of full recovery in adjustment disorder is usually excellent. 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. the feigning of symptoms is under voluntary control. and controlled studies. a history of antisocial behavior and substance abuse. Pharmacotherapy of posttraumatic stress disorder (PTSD) Selective serotonin reuptake inhibitors (SSRIs) General indications: First-line treatment. once/day dosing. and environmental factors. panic attacks develop after the PTSD and are cued solely by traumatic stimuli. Factitious disorder may present with physical or psychological symptoms. irritability. then the diagnosis of adjustment disorder is not made. SSRIs and other serotonergic agents have emerged as the first-line pharmacological treatment of PTSD (Table 12–34). Psychological symptoms are extremely common after mild closed head injuries. and so forth. and emotional lability after a head injury with concussion. acute onset after a trauma. Malingerers often reveal an inconsistent history..Panic disorder Patients with PTSD may also experience panic attacks. In some patients. claimed distress.e. panic attacks predate the PTSD or do not occur exclusively in the context of stimuli reminiscent of the traumatic event. These symptoms bear no relation to the degree of physical injury. compensation. In some patients. The so-called postconcussion syndrome comprises the symptoms of headache. These are summarized in the following sections. and there is often a discrepancy between history. Chronic factitious disorder with physical symptoms (i. especially for intrusive symptoms Other medications General indications: When response to first-line options not adequate. although the motivation for each condition differs. are absent. in recent years. Adjustment disorder differs from PTSD in that the stressor is usually less severe and within the range of common experience. PTSD differs from this by its absence of fabricated symptoms. Compensation neurosis (factitious disorder and malingering) Both factitious disorder and malingering involve conscious deception and feigning of illness. and the motivation is to assume the "patient" role. Malingering involves the conscious fabrication of an illness for the purpose of achieving a definite goal such as money. and objective data. even without loss of consciousness. unexpected symptom clusters. Signs and symptoms may include a wide variety of disturbances and emerge within 3 months of the stressful event. documented efficacy. open clinic trials. . however. and absence of a bizarre pretraumatic medical history. psychological. dizziness. and the characteristic symptoms of PTSD.

and placebo reported modest benefits. after two large controlled trials documented its efficacy. J. A small double-blind trial of mirtazapine monotherapy. an 8-week randomized. Shay 1992). and violent outbursts (Hogben and Cornfield 1981). Marshall (1975). roughly two-thirds of patients in both treatment groups still met criteria for PTSD. 1991b.5 times greater than during continued fluoxetine treatment (Davidson et al. anxiety. Very similar results were reported in another large multicenter sertraline study with very similar design (Davidson et al. and avoidance did not change with desipramine therapy (Reist et al. respectively (Davidson et al. Newer serotonergic antidepressants other than SSRIs may also be beneficial. Tricyclic antidepressants A positive effect of imipramine on posttraumatic night terrors was reported by J. tiagabine. with response rates of 30%. with a 60% responder rate. topiramate. 1991. with large reductions in PTSD symptoms (Chung et al. 2001). Subsequently. 1990) conducted a 4. Davidson et al. 1992. and 20%. D. lamotrigine. Marshall et al. only depressive symptoms improved. in dosages of 45–75 mg/day. 2004). dilantin): mostly open trials showing some efficacy Buspirone: efficacy in an open trial Triiodothyronine: improvement in small open trial. 2006). Currently. 2001) have also reported efficacy. especially for arousal and numbing symptoms (van der Kolk et al. There may also be benefit to continuing SSRI treatment beyond the initial 6-month period. fluoxetine led to a significant reduction of PTSD symptomatology. but not reexperiencing. sertraline (150 mg/day). with 42% of treated patients experiencing at least a 30% symptom improvement (English et al. startle reactions. intrusive symptoms. Subsequently. decrease in intrusive and avoidant symptoms was apparent only in a subgroup of patients who completed 8 weeks of amitriptyline and was marginal. The responder rate was more than 50%. crossover study of desipramine and placebo in 18 veterans with PTSD. 1987. 1989). one double-blind discontinuation study found that relapse on placebo was about 3. McDougle et al. R. in 186 adults with chronic PTSD showed significant improvement in all three symptom clusters compared with placebo. 2000). A controlled comparison of venlafaxine extended-release (mean dosage. diphenhydramine: sleep disturbance Serotonin reuptake inhibitors SSRIs have become established as first-line medications for PTSD treatment (D. 20–40 mg/day.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. significantly higher than the 20% placebo responder rate (Davidson et al. A randomized. sertraline at dosages of 50–200 mg/day resulted in significant benefits that began to manifest by week 2. 34 mg/day) and sertraline (100 mg/day) reported comparable outcomes at 6 weeks. double-blind trial compared . controlled trial of paroxetine. 2001). In a 12-week multicenter placebo-controlled trial. 24%. Sertraline has also been shown to prevent relapse during a double-blind 6-month discontinuation study (Davidson et al. Open trials of fluvoxamine (De Boer et al. 2005). benzodiazepines. sertraline is FDA approved for the treatment of PTSD. and improvement in both numbing and arousal symptoms. Stein et al. 2003). Positive effects of phenelzine on intrusive posttraumatic symptoms have been reported in subsequent small open trials (Davidson et al. Several initial open trials of fluoxetine had reported marked improvement in PTSD symptoms at a wide range of dosages (Davidson et al. at dosages up to 45 mg/day. In a 4-week doubleblind. as well as better social and occupational functioning (R. flashbacks. valproate. at the end of the study. 2001). possibly antidepressant response Trazodone. Monoamine oxidase inhibitors An early study of MAOIs described five cases of "traumatic war neurosis" in whom 8 week double-blind comparison of amitriptyline and placebo in 46 veterans with PTSD. Controlled studies of TCAs in PTSD have not overall reported much success in decreasing posttraumatic symptoms. improved traumatic dreams. was significantly greater with sertraline than with placebo (Brady et al. 2006). Neylan et al. in a double-blind trial comparing fluoxetine and placebo. van der Kolk 1983). 1994). A randomized comparison of mirtazapine (mean dosage. An open citalopram trial reported more modest efficacy. levetiracetam. 225 mg/day). reported a responder rate of 65%. Although depression and anxiety decreased. 2006).

In an initial 6-week trial of prazosin in 5 patients given 1–4 mg/day. 1999). Valproic acid was initially reported to decrease irritability and angry outbursts in two veterans with PTSD (Szymanski and Olympia 1991). In a randomized study of about 40 patients. B. but benefits can also occur for daytime symptoms. all patients had normal electroencephalograms. (1988) reported decreased impulsivity and angry outbursts in 10 veterans who were also treated with carbamazepine. Other medications A small open trial of buspirone reported that seven of eight patients experienced a significant reduction in PTSD . with a rapid median response interval of 9 days (Berlant 2004). 2006). 1988) and found that phenelzine tended to be superior to imipramine. 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. However. improved sleep. Eight patients reported improvements in their capacity to control their emotions and lessened explosiveness. propranolol 40 mg qid or placebo was administered for 10 days within 6 hours of the trauma. imipramine (240 mg). B. as well as psychosocial improvement. difficulty falling and staying asleep. 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. 1999b). Taylor et al. In a retrospective treatment review of Cambodian patients with PTSD. more patients appeared to respond to lamotrigine (Hertzberg et al. as well as in a case series at a mean dosage of 8 mg/day (F. Dilantin was reported effective in one open 12-week trial in 9 adult patients (Bremner and Vermetten 2004). Clark et al. the 1-adrenergic antagonist prazosin has emerged as a very promising agent in the treatment of PTSD. and a majority reported improvements in sleep and nightmares. all showed moderate to marked improvement in PTSD. Dosages of 0. PTSD symptoms were assessed 1 month posttrauma. and placebo in 34 veterans with PTSD (Frank et al. there have been no controlled trials. pilot use of prazosin during the day in an open trial revealed possible clinical benefit with decreased psychological distress to trauma cues (F. 2003). 2002). Wolf et al. with increasing likelihood of remission during continuation treatment (Connor et al. this finding warrants larger studies of lamotrigine. These findings support the role of noradrenergic hyperactivity in the maintenance of autonomic arousal symptoms in PTSD. and a decrease in intrusive thoughts. More recently. a noradrenergic 2 agonist. placebo-controlled crossover trial. 2006b). and it appeared that propranolol may have a preventive effect.4 mg/day of clonidine were administered over a 6-month period. at a median dosage of 50 mg/day about three-fourths of patients were rated as responders after 4 weeks. 2006). In an open trial of carbamazepine in 10 patients with PTSD. 1984) using clonidine. In a very small placebo-controlled trial of lamotrigine at dosages up to 500 mg/day. van der Kolk (1983) reported improvement in intrusive recollections and irritability in more than half of the patients treated. Adrenergic blockers Kolb et al. Recently. Dosage ranged from 120 to 160 mg daily. (1984) treated 12 Vietnam veterans with PTSD in an open trial of the -blocker propranolol over a 6-month period. 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. 10 war veterans were treated with bedtime prazosin at a mean dosage of 10 mg/day. Taylor and Raskind 2002). and intrusive thinking. The most marked improvement with phenelzine was in intrusive symptoms. Topiramate also looked promising in treating PTSD in one open trial of 33 civilians with chronic nonhallucinatory PTSD.2–0. D. which showed a 60% average reduction. fewer nightmares. Mood stabilizers and anticonvulsants In a small open trial of lithium for treating PTSD. whereas another 8-week open trial of valproate monotherapy reported no benefits (Otte et al. and startle. with a 56% responder rate in a retrospective analysis of patients with treatment-resistant PTSD (Kinrys et al. was conducted with nine Vietnam veterans with PTSD. Eleven patients reported a positive change in self-assessment at the end of the 6-month period. and lowered startle.phenelzine (71 mg). with less explosiveness. B. Evidence supporting its use is mostly available for bedtime administration. 2004). resulting in significant improvement in nightmares. hyperalertness. Taylor 2003). Another open pilot study by this group (Kolb et al. with at least moderate improvement of nightmares (F. (1986) reported moderate to great improvement in intrusive symptoms in 7 patients. Tiagabine was also reported effective in a 12-week acute treatment trial. although findings were not very robust (Pitman et al. Levetiracetam was reported to be an effective augmentation. 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. Lipper et al. hyperalertness. In a double-blind. and overall PTSD severity (Raskind et al.

A larger. it may allow for briefer intervention. anxiety. and planning for termination with a reexperiencing of loss are all important therapeutic issues in the treatment of PTSD. 2004). Clark et al. Crisis intervention shortly after the traumatic event is effective in reducing immediate distress and possibly preventing chronic or delayed responses. 5) sensitivity to transference/countertransference issues. Gupta et al. placebo-controlled augmentation trial using risperidone to treat chronic PTSD also reported beneficial reductions in symptoms of PTSD. but there are no controlled studies (Duffy and Malloy 1994). The cortisol treatment resulted in a moderate decline in traumatic memories and reexperiencing symptoms (Aerni et al. van der Kolk 1987b). 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. 2004). Low-dosage cortisol has also been tried in treating PTSD. An open quetiapine augmentation trial. 1989. 1998). however. using a mean dosage of 100 mg/day. 2001). 2005). (1989) emphasized the importance of validating the patient's traumatic experiences as a precondition for reparation of damaged self-identity. triiodothyronine was reported to result in significant clinical improvement in four of five PTSD patients who had only partial responses to SSRIs. in traumatized patients (van der Kolk 1987a). Herman et al. revision of the patient's inner model of self and world. The therapist must establish a working alliance that allows the patient to work through his or her reactions. 2005). resulted in an approximately 25% decline in PTSD symptom severity (Hamner et al. 6) understanding of secondary gain. such patients are often mistrustful and . In one study using a double-blind crossover design. low-frequency. An open trial with risperidone. and psychoticspectrum positive symptoms (Bartzokis et al. developmental difficulties. 1999a.symptoms. or as the central treatment mode. Establishment of a safe and communicative relationship. 3) affective modeling. it remains unclear whether this was not primarily an antidepressant response (Agid et al. reappraisal of the traumatic event. 1998). Psychotherapy General principles It is generally agreed that some form of psychotherapy is necessary in the treatment of posttraumatic pathology. and if the pathological response is still tentative. three patients with chronic PTSD received cortisol 10 mg/day for 1 month. Because of past experiences. D. 24 PTSD patients were assigned to high-frequency. An open trial of bupropion in PTSD reported global improvement secondary to decreased depression. 2005). Atypical antipsychotics can also be useful in treating PTSD. Therefore. Embry (1990) outlined seven major parameters for effective psychotherapy in war veterans with chronic PTSD: 1) initial rapport building. In a small open trial. 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. Cohen et al. 2003). and defensive styles that render the person especially vulnerable to traumatization by particular experiences is central to the treatment of traumatic syndromes. Cyproheptadine has been reported to greatly decrease the nightmares characteristic of PTSD (R. the high-frequency group showed marked improvement in PTSD core symptoms and in anxiety (H. but PTSD symptoms remained mostly unchanged (Canive et al. 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. Group psychotherapy can also serve as an important adjunctive treatment. 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. Transcranial magnetic stimulation TMS was found to have some transient efficacy in decreasing core PTSD symptoms in 10 patients treated openly (Grisaru et al. 4) defocusing on stress and focusing on current life events. Brief dynamic psychotherapy has been advocated both as an immediate treatment procedure and as a way of preventing chronic disorder. in veterans with psychotic PTSD led to an overall improvement of both PTSD and psychotic symptoms (Kozaric-Kovacic et al. and 7) therapist's maintenance of a positive treatment attitude. 1998). 2) limit setting and supportive confrontation. attempting to modify preexisting conflicts. Quetiapine may be helpful in improving the sleep disturbance associated with the disorder (Robert et al. but not enough is known yet about guidelines and recommendations. or sham TMS to the right dorsolateral prefrontal cortex for a total of 10 sessions. 2–4 mg/day. In a randomized and blinded study. Krystal 1968.

both the behavioral and the cognitive treatment resulted in marked improvement. anxiety. also referred to as cognitive reprocessing or restructuring. In yet another treatment study of female rape victims. effects that may be particularly efficacious in PTSD. identifying distorted and maladaptive cognitions and replacing them with more realistic ones (Resick et al. a form of extended repeat exposure to the same traumatic memory over a series of sessions. Progressive muscle relaxation involves contracting and relaxing various muscle groups to induce the relaxation response. 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. their combination. with gains maintained after 6 months. 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). with the two treatments. Drug treatment has been impressionistically reported to have a positive impact on psychotherapy in 70% of cases. exposure therapy.e.e. support. and the gains were maintained during up to 1-year follow-up (Foa et al.. if tolerated. they will become habituated or deconditioned to the stimulus. and self-guided dialogue. and a control waiting list were compared in assaulted women with chronic PTSD. whereas the identification. Relaxation. 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. This is based on the principle that when patients are gradually exposed to a phobic or anxiety-provoking stimulus. combined with elements of distraction. 1998).reluctant to depend on authority figures. Cognitive processing therapy was shown to be more efficacious than wait-list control in a study of women with childhood sexual abuse (Chard 2005).. and hopefulness of peer settings can facilitate therapeutic change. 1986). and simple relaxation techniques. Prolonged exposure. When a phobia or phobic anxiety is associated with PTSD. although not complete remission. whereas their combination was of no additional benefit and relaxation treatment yielded only modest improvement (Marks et al. and insomnia. Relaxation techniques produce the beneficial physiological result of reducing motor tension and lowering the activity of the autonomic nervous system. Numerous studies have documented the effectiveness of all of these psychotherapies in treating PTSD. Generally speaking. is a technique known as stress inoculation training. in vivo desensitization). systematic desensitization or graded exposure has been found to be effective. 2000). stress inoculation training. with cognitive therapy . A randomized trial comparing imaginal exposure with cognitive therapy in 72 patients with chronic PTSD (Tarrier et al. 1999) found comparable significant improvement. thought-stopping. 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. their combination. cognitive restructuring. This is useful for symptoms of autonomic arousal such as somatic symptoms. Hypnosis has also been used to induce the relaxation response with success in PTSD. Virtual reality exposure is another computer-based exposure technique that has been piloted in Vietnam veterans and appears promising (Rothbaum et al. Cognitive therapy. 1999). all three active treatments resulted in comparable improvement. Variations of this treatment include using imaginal techniques (i. 2001). both prolonged exposure and cognitive processing led to comparable PTSD improvement compared with a "minimal attention" intervention. involves various cognitive formulations and corrections of patients' traumatic recollections—that is. In another study. Another controlled study in 87 patients with chronic PTSD compared exposure therapy. TABLE 12–35. exposure and cognitive processing have overall comparable effectiveness. imaginal desensitization) and exposure to real-life situations (i. 2002).

overall. A more recent large multisite randomized. other psychotherapeutic approaches can be helpful in PTSD. The question of whether the addition of a cognitive restructuring component further enhances prolonged exposure therapy is an issue on which not everyone agrees. 2001). 2002). There continues to be some controversy in the literature regarding the efficacy of EMDR as well as its underlying mechanisms of action. shame. KEY POINTS Anxiety disorders are prevalent in the general population. Cohen et al. Serotonin reuptake inhibitors are the first-line treatment for all anxiety disorders. and relaxation training found similar reductions in anger and guilt at the end of treatment and at 3-month follow-up (Stapleton et al. Comparable efficacy between EMDR and prolonged exposure with stress inoculation was found by another study (C. delivered over only three sessions to a very large sample of 168 women with histories of assault or sexual abuse. depression. 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. also appears to be beneficial. 2002). However. 2006). 1998). A. in a randomized study of adult women with PTSD and childhood sexual abuse who were already receiving individual psychotherapy and pharmacotherapy. in which there is evidence of a hyperactive orbitofrontal-limbic-basal ganglia-thalamic circuitry. cognitive processing. Other Psychotherapies In addition to the more mainstream prolonged exposure. controlled psychotherapy trials for PTSD (Bisson and Andrew 2005) concluded. relaxation. Another study comparing exposure therapy. A pilot open trial of interpersonal psychotherapy adapted for treating PTSD also reported benefits (Bleiberg and Markowitz 2005). Imagery rehearsal therapy. CBT appears to also be highly beneficial for children and adolescents. 2005a). 2005). Lee et al. and abuse-related attributions (J. the study also reported that CBT conducted by therapists with minimal CBT experience was just as effective as that conducted by CBT experts. with lifetime prevalence ranging from about 2%–3% for panic disorder and OCD to 15% for social anxiety disorder. and cognitive restructuring are the main types of psychotherapies helpful in treating the anxiety disorders.demonstrating somewhat better outcome for guilt reduction (Resick et al. another similar study of 171 female assault survivors compared two active treatments. SUGGESTED READINGS . In an open trial of CBT in 17 children with PTSD. Exposure. and its superiority became even more apparent at 3-month follow-up (Devilly and Spence 1999). Brief eclectic psychotherapy is a manualized therapy found effective in police officers in a randomized trial (Lindauer et al. resulted in a marked decrease in chronic nightmares (Krakow et al. In a 5-year follow-up study of a small group of veterans who had initially been treated with EMDR with modest benefits. A randomized study comparing EMDR with CBT found that CBT was significantly more effective. and relaxation techniques. 2000). Eye movement desensitization and reprocessing (EMDR) is a technique that has been extensively applied to the treatment of trauma-related pathology. 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. more than half no longer met disorder criteria after treatment and were doing even better at 6-month follow-up (March et al. prolonged exposure alone and prolonged exposure plus cognitive restructuring. behavior problems. Importantly for clinicians. with a wait-list control and found that adding cognitive restructuring did not enhance the effectiveness of the exposure (Foa et al. Another approach. 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. EMDR. The "neurocircuitry of fear" has been implicated in all anxiety disorders except for OCD. affect management. 1997). that both trauma-focused CBT and stress management therapy were significantly more effective than non–trauma focused usual-care therapies or wait-list assignment. 2004). 1998a). Anxiety disorders are highly treatable: medication and CBT constitute first-line treatments for all these disorders. EMDR was found to be superior to relaxation in treating PTSD in one study (Carlson et al. 2003). all benefit was lost at follow-up (Macklin et al. yet the combined treatment led to greater reduction in PTSD symptoms and in maladaptive cognitions than exposure alone (Bryant et al. A meta-analysis of randomized.

Shalev AY. Biol Psychiatry 49:588–595. 2004 [Full Text] [PubMed] Agid O. 2005 [PubMed] Adams KH. et al: Right prefrontal repetitive transcranial magnetic stimulation in obsessive compulsive disorder: a double blind.Barlow DH: Clinical Handbook of Psychological Disorders: A Step-by-Step Treatment Manual. et al: Patients with obsessive compulsive disorder have increased 5-HT2A receptor binding in the caudate nuclei. Pujol J. Am J Med Genet 88:699–675. et al: Low dose cortisol for symptoms of posttraumatic stress disorder. Lerer B: Triiodothyronine augmentation of selective serotonin reuptake inhibitors in posttraumatic stress disorder. 2002 Yehuda R: Treating Trauma Survivors With PTSD. et al: Blunted growth hormone response to clonidine in patients with generalized anxiety disorder. 1999 Altemus M. Austin C. New York. placebo controlled study. 2004 [Full Text] [PubMed] Alonso P. 1975 [PubMed] Alden LE. McDonough-Ryan P. Hollander E: The American Psychiatric Publishing Textbook of Anxiety Disorders. Craske MG: Cognitive theories of generalized anxiety disorder. Stein DJ (eds): Obsessive Compulsive Disorders. Rapee RM: Post event rumination and negative self appraisal in social phobia before and after treatment. Leonard HL. Cardoner N. Am J Psychiatry 150:460–464. New York. Marcel Dekker. 1995 [PubMed] Allgulander C. 2002 REFERENCES Abbott MJ. 2001 [PubMed] Aikins DE. Pigott T. J Abnorm Psychol 113:136–144. American Psychiatric Publishing. 2003 Stein DJ. 2001 [PubMed] Akhtar S. DC. Bakalar N: Coping With Social Anxiety: The Definitive Guide to Effective Treatment Options. Varma VK. DC. Dahl AA. Biol Psychiatry 57:510–516. et al: Changes in cerebrospinal fluid neurochemistry during treatment of obsessive- . 1997 Horowitz MJ: Treatment of Stress Response Syndromes. 1991 [PubMed] Allgulander C. Am J Psychiatry 161:1488–1490. et al: Persistent respiratory irregularity in patients with panic disorder. Washington. Arch Gen Psychiatry 48:157–162. Guilford. Washington. Sax KW. 3rd Edition. et al: Deep brain stimulation for refractory obsessive-compulsive disorder. Washington. New York. DC. American Psychiatric Publishing. 2001 [PubMed] Abelson JL. Leckman JF. Goodman WK. 2000 [PubMed] Aerni A. Arch Gen Psychiatry 48:599–602. Int J Neuropsychopharmacol 8:391–401. et al: A phenomenological analysis of symptoms in obsessive-compulsive neurosis. Psychiatr Clin North Am 24:57–74. Behav Res Ther 33:497–505. Weg JG. L'Heureux F. Glitz D. Am J Psychiatry 158:1143–1144. Lavori PW: Excess mortality among 3302 patients with "pure" anxiety neurosis. Hansen ES. Curtis GC. 2001 [Full Text] [PubMed] Alsobrook JP II. 1991 [PubMed] Abelson JL. Simeon D: Concise Guide to the Anxiety Disorders. Cameron OG. 2005 [PubMed] Adler CM. Wig NN. J Clin Psychiatry 62:169–173. 2005 Hollander E. American Psychiatric Publishing. DC. Wallace ST: Social phobia and social appraisal in successful and unsuccessful social interactions. et al: CSF somatostatin in obsessive-compulsive disorder. et al: fMRI of neuronal activation with symptom provocation in unmedicated patients with obsessive compulsive disorder. Swedo SE. Traber R. Washington. 1993 [Full Text] [PubMed] Altemus M. American Psychiatric Publishing. Henry Holt and Company. J Psychiatr Res 34:317–324. Nesse RM. et al: Efficacy of sertraline in a 12-week trial for generalized anxiety disorder. Br J Psychiatry 127:342–348. 2004 [PubMed] Abelson JL. 2001 Hollander E. Pinborg LH. et al: Segregation analysis of obsessive-compulsive disorder using symptom-based factor scores. Am J Psychiatry 161:1642–1649. Sagher O. 2003 Hollander E. Hock C.

van den Hout M: Psychological treatments of panic disorder without agoraphobia: cognitive therapy versus applied relaxation. 1996 [PubMed] Aschenbrand SG. 1980 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. Williams & Wilkins. Adrover M. 2004 [PubMed] Arntz A: Cognitive therapy versus interoceptive exposure as treatment of panic disorder without agoraphobia. 3rd Edition. American Psychiatric Association. Washington. 2003 [PubMed] Amir N. Brain Res 191:583–588. Foote FE. Washington. 2002 [PubMed] Arntz A: Cognitive therapy versus applied relaxation as treatment of generalized anxiety disorder. DC. Elias J. Tezcan E. Clement MH. J Am Acad Child Adolesc Psychiatry 42:1476–1485. Hood SD. American Psychiatric Association. Washington. Behav Res Ther 34:113–121. Ratzoni G. 2000 Amir N. Behav Res Ther 41:1325–1335. Klumpp H. Klumpp H. Rosenberg DR. Hameedi FA. American Psychiatric Association. et al: Is childhood separation anxiety a predictor of adult panic disorder and agoraphobia? A seven-year longitudinal study. et al: The effect of practice on recall of emotional information in individuals with generalized social phobia. Psychiatry Res 103:1–14. 1987 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. Goddard AW. 2003 [PubMed] Arntz A. American Psychiatric Association. Pizzino A. norepinephrine depletion and escape performance. 4th Edition. J Abnorm Psychol 114:402–408. Washington. American Psychiatric Association. 2nd Edition. Elias J. Lake CR. 2001 [PubMed] Aston-Jones SL. Coles ME. Revised. DC. 1984. Biol Psychiatry 57:975–981. J Am Acad Child Adolesc Psychiatry 33:342–348. Brigidi B. Bloom FE: Norepinephrine. et al: Increased activation of the anterior cingulated cortex during processing of disgust faces in individuals with social phobia. Brown TA. J Abnorm Psychol 110:76–82. 3rd Edition. 2005a Amir N. Sklar LS: Coping with stress. panic disorder. 1997 [Full Text] [PubMed] Apter A. DC. Behav Res Ther 40:325–341. 1994 [PubMed] American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. 1968 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. 1994 [PubMed] Argyropoulos SV.compulsive disorder with clomipramine. Kendall PC. 2005b Anisman HL. King RA. DC. Vol 2. et al: Fluvoxamine in the treatment of panic disorder: a multi-center. Text Revision. 1980 [PubMed] Antony MM. et al: Tryptophan depletion reverses the therapeutic effect of selective serotonin reuptake inhibitors in social anxiety disorder. et al: Association of a glutamate (NMDA) subunit receptor gene (GRIN2B) with obsessive compulsive disorder: a preliminary study. 1994 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. Przeworkski A: Resolving ambiguity: the effect on interpretation of ambiguous events in generalized social phobia. placebo-controlled study in outpatients. Beard C. et al: Amygdala response in patients with cute PTSD to masked and unmasked emotional facial expressions. DC. Webb A. MD. Corbo V. pp 92–116 Atmaca M.5% carbon dioxide inhalation of subjects with types of specific phobia. Washington. in Frontiers of Clinical Neuroscience. 2001 [PubMed] Amir N. Edited by Ziegler. 4th Edition. Kuloglu M. Psychopharmacology 174:530–538. 2005 [Full Text] [PubMed] Arnold PD. et al: Quetiapine augmentation in patients with treatment resistant obsessive . Mundo E. 2003 Asnis GM. doubleblind. or no mental illness. Barlow DH: Response to hyperventilation and 5. Biol Psychiatry 56:503–509. Baltimore. 2004 [PubMed] Armony JL. Arch Gen Psychiatry 51:794–803. et al: Attentional bias to threat in social phobia: facilitated processing of threat of difficulty disengaging attention from threat. et al: Fluvoxamine open-label treatment of adolescent inpatients with obsessivecompulsive disorder or depression. Behav Res Ther 41:633–646. Am J Psychiatry 154:1089–1095. Am J Psychiatry 162:1961–1963.

Behnke K. et al: Behavioral treatment of panic disorder. 2002 [PubMed] Bandelow B. fixed-dose. et al: Paroxetine in social phobia/social anxiety disorder: a randomized. New York. 2002 [PubMed] Barr LC. 1992 Barlow DH. Am J Psychiatry 154:1293–1295. Schwartz JM. Kilic C. et al: Efficacy of olanzapine in social anxiety disorder: a pilot study. 2000 Bandelow B. Bergman KS. Am J Psychiatry 155:36–42. 1995 [PubMed] Baker DG. parental attitudes. 1994 [PubMed] Baxter LR Jr. et al: Virtual reality in treatment of flying phobia. 2006 [PubMed] Bartzokis G. Bobes J. Gorman JM. J Clin Psychiatry 65:405–413. 2000 [PubMed] Barnett SD. et al: Caudate glucose metabolic rate changes with both drug and behavior therapy for obsessive-compulsive disorder. 2002 [PubMed] Barlow DH: Anxiety and Its Disorders: The Nature and Treatment of Anxiety and Panic. 1997 [Full Text] [PubMed] Bartz JA. J Clin Psychiatry 66:94–99. Rosenberg DR: Use of low dose selective serotonin reuptake inhibitors for severe. et al: Cingulotomy for intractable obsessive-compulsive disorder. et al: A crossover study of focused cognitive therapy for panic disorder. Kramer ML. refractory choking phobia in childhood. Phelps ME. IEEE Trans Inf Technol Biomed 6:206–212. et al: Cognitive-behavioral therapy. Br J Psychiatry 175:120–126. Clark DA. J Psychopharmacol 16:365–368. 2005 [PubMed] Basoglu M. double-blind noninferiority comparison. Arch Gen Psychiatry 52:384–392. Steiner M. Guilford. Int Clin Psychopharmacol 17:115–119. 2004 [PubMed] Banerjee SO. Shear MK. Kuhn A. Stein DJ. Turner J: Adjunctive risperidone in the treatment of chronic combat related posttraumatic stress disorder. Brown TA: Behavioral treatment of generalized anxiety disorder. et al: Higher levels of basal serial CSF cortisol in combat veterans with posttraumatic stress disorder. placebo controlled study. Ballantine HT. Rauch SL. 2005 [PubMed] Banos RM. Biol Psychiatry 57:474–479. Perpina C. 1992 [PubMed] . Goodman WK. JAMA 283:2529–2536. Rapee RM. Lu PH. prospective comparison between paroxetine and sertraline. Arch Gen Psychiatry 44:211–218. et al: Early traumatic life events. Casat CD. 1988 Barlow DH. placebo-controlled study of paroxetine in the treatment of panic disorder. or their combination for panic disorder: a randomized controlled trial. Hollander E: Is obsessive compulsive disorder an anxiety disorder? Prog Neuropsychopharmacol Biol Psychiatry 30:338–352. Behav Ther 20:261–282. et al: Local cerebral glucose metabolic rates in obsessive-compulsive disorder: a comparison with rates in unipolar depression and in normal controls. Botella C. 2005 [PubMed] Ballenger JC. anticipatory anxiety. Marks IM. imipramine. Spath C. Arch Gen Psychiatry 49:681–689. Acta Psychiatr Scand 106:163–167. 2002 [PubMed] Baer L. et al: Relationship of panic. Am J Psychiatry 149:778–783. Wall D. 1999 [PubMed] Ball SG. Br J Psychiatry 164:647–652. 1989 Barlow DH. Compr Psychiatry 43:269–278. et al: Selective serotonin reuptake inhibitor treatment for generalized anxiety disorder: a double-blind. 1992 [PubMed] Baer L. Prospective long-term follow-up of 18 patients. TCAs in the treatment of panic disorder: a meta-analysis. Lenoir S. Sokol L. Spinhoven P: SSRIs vs. Bhandari RP. Craske MG. Mazziotta JC. 2002 [PubMed] Baldwin D. et al: Double-blind. Tichauer GA. Kasckow JW. Jenike MA: Personality disorders in obsessive-compulsive disorder. Anand A. 2005 [Full Text] [PubMed] Bakker A. and birth risk factors in patients with panic disorder. et al: Sertraline versus paroxetine in the treatment of panic disorder: an acute.compulsive disorder: a single blind. 1987 [PubMed] Baxter LR Jr. placebo-controlled study. J Dev Behav Pediatr 26:123–127. 1992 [PubMed] Beck AT. Behav Ther 23:551–570. Cerny JA. Ekhator NN. van Balkom AJ. Am J Psychiatry 162:992–994. double-blind. family history. Psychiatr Clin North Am 15:803–812. agoraphobia and global improvement in panic disorder with agoraphobia treated with alprazolam and exposure. et al: Addition of desipramine to serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder. Wheadon DE.

Biol Psychiatry 59:853–857. Markowitz JC: A pilot study of interpersonal psychotherapy for posttraumatic stress disorder. Grodd W. J Consult Clin Psychol 68:1072–1080. et al: Lack of effects on core obsessive compulsive symptoms of tryptophan depletion during symptom provocation in remitted obsessive compulsive disorder patients. Morris TL: Behavioral treatment of childhood social phobia. Andrew M: Psychological treatment of post-traumatic stress disorder. 2005 [PubMed] Brady K. Asnis GM. Am J Psychiatry 154:1566–1570. 1993 [PubMed] Bouwer C. 2004 [PubMed] Berney A. London. Br J Psychiatry 187:352–359. McCafferty JP. Karbofsky E. Nutt DJ: The neurobiology of social phobia. Presented at the annual meeting of the American Psychiatric Association. Samuels JF. Neumeister A. King N. Basic Books. Ahokas A. Iyengar M. 1998 [PubMed] Bowlby J: Attachment and Loss. et al: Double-blind. 1992 [PubMed] Bleiberg KL. 1973 Bradwejn J. Noyes R. crossover trial of inositol treatment for panic disorder. Ben-Zion IZ. Cora-Locatelli G. Arch Gen Psychiatry 49:362–368. Bain E. Mol Psychiatry 2:403–406. Fux M. placebo-controlled study. et al: No change in serotonin type 1A receptor binding in patients with posttraumatic stress disorder. 1999 [PubMed] Benjamin J. Malizia AL. Costello E: Efficacy of applied relaxation and cognitive-behavioral therapy in the treatment of generalized anxiety disorder. Neuroreport 9:1223–1226. BMC Psychiatry 4:24. et al: Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial. Leyton M. 2005 Black A: The natural history of obsessional neurosis. 1995 [Full Text] [PubMed] Benjamin J. Stein DJ: Association of panic disorder with a history of traumatic suffocation. Vol 2: Separation: Anxiety and Anger. 1999 Bellew KM. Garb R. Mol Psychiatry 4:463–466. New York. 2005 [Full Text] [PubMed] Bleich A. Eur Arch Psychiatry Clin Neurosci 249:S11–S18. J Consult Clin Psychol 61:611–619. 2000 [PubMed] . placebo-controlled trial. 1997 [Full Text] [PubMed] Bouwer C. England. in Obsessional States. et al: Association of the serotonin transporter promoter regulatory region polymorphism and obsessive-compulsive disorder. 1997 Birbaumer N. et al: A family study of obsessive-compulsive disorder. et al: Obsessive compulsive disorder. Biol Psychiatry 48:287–293. Stein DJ. Goldstein RB. Chicago. 1986 [PubMed] Bonne O. Am J Psychiatry 162:181–183. Greenberg BD. response to serotonin reuptake inhibitors and the serotonin transporter gene. Psychopharmacology (Berl) 149:194–196. pp 19–54 Black DW. Richter MA. placebo-controlled study of paroxetine for specific phobia. 2000 [PubMed] Billet EA. Diedrich O. Cochrane Database Syst Rev (2):CD003388. JAMA 283:1837–1844. et al: The relationship of obsessive-compulsive disorder to possible spectrum disorders: results from a family study. doubleblind. et al: fMRI reveals amygdala activation to human faces in social phobics. Pearlstein T. Riddle MA. et al: Post-traumatic stress disorder following combat exposure: clinical features and psychopharmacological treatment. 1998 [PubMed] Bisson J. et al: Venlafaxine extended-release capsules in panic disorder: flexible-dose. 2000 Bengel D. Levine J. et al: Double-blind. J Affect Disord 49:79–82. et al: Paroxetine treatment of GAD: a double-blind. Br J Psychiatry 149:365–369. Siegel B. Am J Psychiatry 152:1084–1086. Turner SM. placebo-controlled. 2006 [PubMed] Bienvenu OJ. 2005 [Full Text] [PubMed] Borkovec TD. Methuen. Am J Psychiatry 162:383–385. Sookman D. 2000 [PubMed] Bell CJ. IL. Stein DJ: Use of the selective serotonin reuptake inhibitor citalopram in the treatment of generalized social phobia. 1974.Beidel DC. 2000 [PubMed] Berlant JL: Prospective open label study of add on monotherapy topiramate in civilians with chronic nonhallucinatory posttraumatic stress disorder. Edited by Beech HK.

1991 [PubMed] Breslau N. et al: Traumatic events and posttraumatic stress disorder in an urban population of young adults. et al: Trauma and posttraumatic stress disorder in the community: the 1996 Detroit Area Survey of Trauma. Nietert PJ: Adjunctive risperidone in generalized anxiety disorder: a double-blind. Southwick SM. et al: Sex differences in posttraumatic stress disorder. 2000 [PubMed] Breslau N. Scott TM. Narayan M. Am J Psychiatry 157:629–631. 2000 [Full Text] [PubMed] . A prospective approach. 1997b Breslau N. et al: Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder. Freud S: Studies on hysteria (1893–1895). London. Ann NY Acad Sci 1032: 154–157. et al: Psychiatric sequelae of posttraumatic stress disorder in women. Arch Gen Psychiatry 53:595–606. Am J Psychiatry 152:973–981. 2005 [PubMed] Bryant RA. Darnell A. Hogarth. Am J Psychiatry 154:624–629. 2004 [PubMed] Bremner JD. et al: Functional magnetic resonance imaging of symptom provocation in obsessivecompulsive disorder. Edited by Strachey J. Kwong KK. Scott TM. et al: SPECT [I-123] iomazenil measurement of the benzodiazepine receptor in panic disorder. Davis GC. Knapp RG. et al: MRI-based measurement of hippocampal volume in patients with combatrelated posttraumatic stress disorder. 1955. Am J Psychiatry 156:1787–1795. Perna G. Crooks J. White T. J Clin Psychiatry 66:1321–1325. et al: Posttraumatic stress disorder after severe traumatic brain injury. 2005 [PubMed] Breiter HC. Arch Gen Psychiatry 54:1044–1048. Andreski P. 1993a Bremner JD. Kessler RC. Arch Gen Psychiatry 54:81–87. Arch Gen Psychiatry 55:626–632.Brambilla F. 1993b Bremner JD. Biol Psychiatry 42:889–897. Biol Psychiatry 48:902–909. Innis RB. Am J Psychiatry 150:1015–1019. Chilcoat HD. Am J Psychiatry 150:235–239. Johansson B. 1992 [PubMed] Breslau N. Am J Psychiatry 149:671–675. England. placebo-controlled study. Vermetten E: Neuroanatomical changes associated with pharmacotherapy in posttraumatic stress disorder. Am J Psychiatry 155:625–629. in The Standard Edition of the Complete Psychological Works of Sigmund Freud. 2000 [PubMed] Breuer T. Davis GC. Arch Gen Psychiatry 48:216–222. et al: Deficits in short-term memory in posttraumatic stress disorder. Peterson EL. 1997b Bremner JD. Davis GC: Posttraumatic stress disorder in an urban population of young adults: risk factors for chronicity. Rauch SL. Delaney RC. Biol Psychiatry 47:96–106. Licinio J. Bellodi L. pp 1–319 Bryant RA: Predicting posttraumatic stress disorder from acute reactions. 1999 [Full Text] [PubMed] Bremner JD. 1999 [PubMed] Bremner JD. Vol 2. Davis GC. Ost LG: Cognitions in generalized anxiety disorder and panic disorder patients. et al: Childhood physical abuse and combat-related posttraumatic stress disorder in Vietnam veterans. 1995 [Full Text] [PubMed] Bremner JD. et al: A second look at comorbidity in victims of trauma: the posttraumatic stress disorder–major depression connection. Harvey AG: Relationship between acute stress disorder and posttraumatic stress disorder following mild traumatic brain injury. 1998 [PubMed] Breslau N. Davis GC. et al: Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. 1997a Bremner JD. Johnson DR. Staib LH. 1998 [Full Text] [PubMed] Bryant RA. Peterson EL. Andreski P. Vermetten E. Marosszeky JE. Randall P. et al: Dopamine function in obsessive-compulsive disorder: growth hormone response to apomorphine stimulation. 1997a Breslau N. 1996 [PubMed] Breitholtz E. Biol Psychiatry 41:23–32. J Trauma Dissociation 6:5–15. Randall P. Behav Res Ther 37:533–544. 1997 [PubMed] Brawman-Mintzer O. et al: Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse: a preliminary report.

Pasquale L. J Consult Clin Psychol 61:248–260. et al: Efficacy and tolerability of mirtazapine and sertraline in Korean veterans with posttraumatic stress disorder: a randomized open label trial. J Consult Clin Psychol 73:965–971. 1998 [PubMed] Chabane N. et al: Genome-wide linkage scan in a large bipolar disorder sample from the National Institute of Mental Health genetics initiative suggests putative loci for bipolar disorder. Depress Anxiety 13:78–88. in Rochester Symposium on Developmental Psychopathology. Moulds ML. Juo SH. Ackerman DL. BMC Psychiatry 5:44. 1981. Bhattacharyya S. et al: Bupropion treatment in veterans with posttraumatic stress disorder: an open study. et al: Approximate entropy of respiratory patterns in panic disorder. 1993 [PubMed] Chard KM: An evaluation of cognitive processing therapy for the treatment of posttraumatic stress disorder related to childhood sexual abuse. Fennell M. Price LH. Breier A: Noradrenergic function in panic anxiety: effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. et al: Positron emission tomography assessment of effects of benzodiazepines on regional glucose metabolic rate in patients with anxiety disorder. Clark RD. 1984 [PubMed] Charney DS. Christopher R. 2004 [PubMed] Chakrabarty K. psychosis. 1988 [PubMed] Chartier MJ. 2001 [PubMed] Cassidy J: Attachment and generalized anxiety disorder. Robson P. Wittchen HU. Neurosci Lett 363:154–156. University of Rochester Press. Stein MB: Social phobia and potential childhood risk factors in a community sample. Wu J.Bryant RA. Gottesman II: Twin and family studies of anxiety. Cognition and Representation. 2003 Buchsbaum MS. and panic disorder. 1995. et al: Glutamatergic dysfunction in OCD. Delorme R. Toth S. 2005 [PubMed] Chambless DL. Psychol Med 31:307–315. Guthrie RM. Arch Gen Psychiatry 45:177–185. Vol 6: Emotion. Haier R. et al: Augmentation of serotonin reuptake inhibitors in refractory obsessive compulsive disorder using adjunctive olanzapine: a placebo controlled trial. Gillis MM: Cognitive therapy of anxiety disorders. New York. J Trauma Stress 11:3–24. Millet B. et al: Eye movement desensitization and reprocessing (EMDR) treatment for combat-related posttraumatic stress disorder. 1991 [PubMed] Bystritsky A. Chemtob CM. 1998 [PubMed] Carter RM. New York. Goodman WK. Mol Psychiatry 11:252–260. Vythilingum B. J Consult Clin Psychol 59:167–175. randomized. Seedat S. Pfister H. 2005 Carlson JG. et al: One-year prevalence of subthreshold and threshold DSM-IV generalized anxiety disorder in a nationally representative sample. Rusnak K. 2006 [PubMed] Chung MY. Neuropsychopharmacology 30:1735–1740. Min KH. J Clin Psychiatry 65:565–568. et al: Serotonin function in obsessive-compulsive disorder: a comparison of the effects of tryptophan and m-chlorophenylpiperazine in patients and healthy subjects. Raven. pp 343–370 Cavallini MC. Walker JR. Hum Psychopharmacol 19:489–494. phobic. Bellodi L. et al: Imaginal exposure alone and imaginal exposure with cognitive restructuring in treatment of posttraumatic stress disorder. J Consult Clin Psychol 7:706–712. Edited by Cicchetti D. 1998 [PubMed] Carey G. et al: Quetiapine augmentation of SRIs in treatment refractory obsessivecompulsive disorder: a double blind. Di-Bella D. suicide. Rabkin J. et al: Comparison of behavior therapy and cognitive behavior therapy in the treatment of generalized anxiety disorder. 2005 [PubMed] Charney DS. placebo controlled study. 2001 [PubMed] Cheng R. Life Sci 40:2393–2400. et al: Lack of evidence for association between serotonin transporter gene (5-HTTLPR) and obsessive compulsive disorder by case control and family association study in humans. J Clin Psychopharmacol 18:379–383. et al: 5HT2C CYS23/SER23 polymorphism is not associated with obsessivecompulsive disorder. Caumo A. Loth JE. pp 117–136 Carey PD. Psychiatry Res 77:97–104. Rosen RM. 2004 [PubMed] Caldirola D. Calais LA. Heninger GR. Arch Gen Psychiatry 41:751–763. Jun YJ. 2004 [PubMed] . 1987 [PubMed] Butler G. Edited by Klein DF. and obsessive disorders. in Anxiety: New Research and Changing Concepts. Am J Psychiatry 161:79–87. 2004 [Full Text] [PubMed] Canive JM.

2004 [Full Text] [PubMed] Cohen JA. Calais LA. et al: Tiagabine for posttraumatic stress disorder: effects of open label and double blind discontinuation treatment. Taskiran S. Canive JM. 2001 [PubMed] Coupland NJ. Cook JL. Biol Psychiatry 58:424–428. Deblinger E. Gysin R: Dopamine D2 receptor (DRD2) gene and susceptibility to posttraumatic stress disorder: a study and replication. et al: Flumazenil challenge in social phobia. Psychother Psychosom 69:137–146. Stein MB. Salkovskis PM. 2000 Cox B. Payne VM. Behav Res Ther 42:105–114. Kotler M. Papp LA. 2005 [PubMed] Crowe RR. Pine D. 1994 [PubMed] Clark RD. Arch Gen Psychiatry 48:730–738. et al: Clinical improvement with fluoxetine therapy and noradrenergic function in patients with panic disorder. Richards JC. et al: The use of aripiprazole in obsessive compulsive disorder: preliminary observations in 8 patients. J Clin Psychiatry 66:49–51. 1995 [PubMed] Coplan JD. J Trauma Stress 12:395–401. et al: Cyproheptadine treatment of nightmares associated with posttraumatic stress disorder. et al: Repetitive transcranial magnetic stimulation of the right dorsolateral prefrontal cortex in posttraumatic stress disorder: a double blind. et al: Divalproex in posttraumatic stress disorder: an open-label clinical trial. Enns MW. Note I. Davidson JR: Botulinum toxin treatment of social anxiety disorder with hyperhydrosis: a placebo controlled double blind trial. 1997 [PubMed] Coric V. et al: A comparison of cognitive therapy. Hackmann A. Davidson JR. 1996 [PubMed] Condren RM. Canive JM. 2005 [PubMed] Coryell W. placebo controlled study. Weisler RH. et al: Riluzole augmentation in treatment resistant obsessive compulsive disorder: an open label trial. Ryan MC. Pine D. 1983 . 1999a Clark RD. 2006a Connor KM. et al: Does the addition of cognitive behavioral therapy improve panic disorder treatment outcome relative to medication alone in the primary-care setting? Psychol Med 35:1645–1654. Psychother Psychosom 70:288–297. Gadde KM. Edwards CJ: Selective attention in obsessive-compulsive disorder. Biol Psychiatry 40:368–372. Anxiety 111:27–30. Kaplan Z. et al: Neuroticism and self criticism associated with posttraumatic stress disorder in a nationally representative sample. Psychoneuroendocrinology 27:693–703. 1999b Clayton IC. Fyer A. Pittenger C. Am J Psychiatry 161:515–524. Note I. 2005 [PubMed] Connor KM. Arch Gen Psychiatry 54:643–648. O'Neill A. Muhleman D. Albuisson E. 2004 [PubMed] Craske MG. Mannarino AP. Bell C. et al: A family study of panic disorder.Clark DM. Pine D. 2004 [PubMed] Comings DE. randomized controlled trial for children with sexual abused related PTSD symptoms. et al: Uncoupling of the noradrenergic-hypothalamic-pituitary-adrenal axis in panic disorder patients. 2001 [PubMed] Cottraux J. et al: A multisite. Papp L. et al: Cognitive behavior therapy versus supportive therapy in social phobia: a randomized controlled trial. 2000 [PubMed] Cottraux J. J Clin Psychiatry 67:30–36. Arch Gen Psychiatry 40:1065–1069. Yao SN. J Abnorm Psychol 108:171–175. 1991 Cohen H. 2006b Cooper AM: Will neurobiology influence psychoanalysis? Am J Psychiatry 142:1395–1402. et al: HPA axis response to a psychological stressor in generalized social phobia. et al: A randomized controlled trial of cognitive therapy versus intensive behavior therapy in obsessive compulsive disorder. 1985 [PubMed] Coplan JD. applied relaxation therapy and imipramine in the treatment of panic disorder. et al: Aberrant respiratory sensitivity to CO(2) as a trait of familial panic disorder. Noyes R. MacPherson PS. Biol Psychiatry 49:582–587. Calais LA. Golinelli D. J Clin Psychopharmacol 19:486–487. Psychopharmacology (Berl) 184:21–25. 1999 [PubMed] Clomipramine Collaborative Study Group: Clomipramine in the treatment of patients with obsessive-compulsive disorder. Potokar J. J Am Acad Child Adolesc Psychiatry 43:393–402. 2002 [PubMed] Connor KM. Br J Psychiatry 164:759–769. Neuropsychopharmacol 13:65–73. Pauls DL.

J Am Acad Child Adolesc Psychiatry 37:1022–1029. Tucker P. 2006 [PubMed] Davis LL. 2005 [PubMed] Dannon PN. Hoogduin KA. 1992 de Haan E. Acta Psychiatr Scand 111:429–435. Biol Psychiatry 53:188–191. Eur Neuropsychopharmacol 10:165–169. Hirschmann S. Arch Gen Psychiatry 58:485–492. safety. 2003 [PubMed] Davidson JR. et al: Sertraline in generalized anxiety disorder: efficacy in treating the psychic and somatic anxiety factors. Lange A. 1995 De Boer M. 1996 [PubMed] Dahl AA. Biol Psychiatry 41:76–85. Allgulander C. Rothbaum BO. Am J Med Genet 105:105–109. Am J Psychiatry 152:683–691. 1991 Davidson J. Kudler H. 2000 [PubMed] Davidson J. Hedges D. Falger PJ. J Abnorm Child Psychol 24:187–203. et al: Family process and child anxiety and aggression: an observational analysis. Dahl RE. 1997 [PubMed] Dadds MR. 1998 DeBellis MD. et al: Behavior therapy versus clomipramine for the treatment of obsessivecompulsive disorder in children and adolescents. Smith R. J Clin Psychopharmacol 26:259–267. 1990 [PubMed] Davidson J. 2000 . et al: Treatment of posttraumatic stress disorder with amitriptyline and placebo. 1987 [PubMed] Davidson J. et al: Fluoxetine. Richichi E. et al: Efficacy. George LK. et al: The epidemiology of social phobia: findings from the Duke Epidemiological Catchment Area Study. J Clin Psychiatry 60:528–535. Roth S. Rothbaum BO. 2004 [PubMed] Davidson JR. et al: Treatment of panic disorder with agoraphobia: comparison of fluvoxamine. and placebo in generalized social phobia. placebo and psychological panic management combined with exposure and of exposure in vivo alone. Butterfield MI. Foa E. et al: Genomewide survey of panic disorder. et al: Incidence of anti-brain antibodies in children with obsessive compulsive disorder. Psychother Psychosom 57:158–163. Hughes DL. Huppert JD. Potts N. 2001 [PubMed] Curtis GC. van der Kolk BA. 2005 [PubMed] Davidson JR. J Clin Psychopharmacol 25:166–169. Connor KM. Sasson Y. Br J Psychiatry 150:252–255. Biol Psychiatry 45:928–930. Kilts C: A pilot study of phenelzine in the treatment of post-traumatic stress disorder. 2005 [PubMed] Dale RC. 2001 [PubMed] Davidson JR. et al: Treatment of social phobia with clonazepam and placebo. DuPont RL. et al: Mirtazapine vs placebo in posttraumatic stress disorder: a pilot trial. 1993b Davidson JR. et al: Multicenter. Arch Gen Psychiatry 61:1005–1013. Barrett PM. double blind comparison of sertraline and placebo in the treatment of posttraumatic stress disorder. Rapee RM.[PubMed] Crowe RR. et al: Venlafaxine extended release in posttraumatic stress disorder: a sertraline and placebo controlled study. Ravindran A. et al: Pindolol augmentation in treatment-resistant obsessive compulsive disorder: a double-blind placebo controlled trial. 1993a Davidson JR. Newman E: Fluoxetine in post-traumatic stress disorder. comprehensive cognitive behavioral therapy. van Balkom AJ. J Trauma Stress 4:419–423. Psychol Med 23:709–718. et al: Maintenance therapy with fluoxetine in posttraumatic stress disorder: a placebo controlled discontinuation study. J Clin Psychopharmacol 13:423–428. Biol Psychiatry 48:51–57. Hertzberg MA. Buitelaar JK. Walker JI. Gold PW: Adrenocorticotropic hormone and cortisol responses to corticotropin-releasing hormone: changes in panic disorder and effects of alprazolam treatment. 1999 [PubMed] Davidson JR. Abelson JL. et al: D-fenfluramine challenge in posttraumatic stress disorder. et al: A pilot study of amygdala volumes in pediatric generalized anxiety disorder. Weisler RH. Br J Psychiatry 187:314–319. Goedken R. Giovannoni G. Kramer GL. Arch Gen Psychiatry 47:259–266. Samuelson S. Clark DM. and tolerability of venlafaxine extended release and buspirone in outpatients with generalized anxiety disorder. Heyman I. Casey BJ. 1999 [PubMed] de Beurs E. Op den Velde W. et al: Fluvoxamine treatment for chronic PTSD: a pilot study.

et al: Frequency and transmission of glutamate receptors GRIK2 and GRIK3 polymorphisms in patients with obsessive compulsive disorder. et al: Antecedents of the risk of recovery from DSM-III-R social phobia. Am J Psychiatry 159:269–274. 2006 [PubMed] Ehlers A. J Anxiety Disord 19:479–502. 1994 [PubMed] Dvorkin A. Nothen MM. Neuroreport 15:699–702. 1997 [Full Text] [PubMed] Embry CK: Psychotherapeutic interventions in chronic posttraumatic stress disorder. et al: Cognitive therapy. van der Wee N. Mol Psychiatry 3:81–85. Psychoneuroendocrinology 30:121–128. DC. Nugent NR. van Megen HJ. 1994 [PubMed] Durham RC. J Clin Psychopharmacol 1:276–277. Janssen J. 2005 [PubMed] Dougherty DD. Offord DR. 1999 Delahanty DL. deGeus F. Chandler Coutts M. Catalano M. placebo-controlled trial of quetiapine addition in patients with obsessive-compulsive disorder refractory to serotonin reuptake inhibitors. et al: A double-blind. et al: Prospective long term follow up of 44 patients who received cingulotomy for treatment refractory obsessive compulsive disorder. Szechtman H: Development and temporal organization of compulsive checking induced by repeated injections of the dopamine agonist quinpirole in an animal model of obsessive compulsive disorder. Dikel TN. Behav Res Ther 38:319–345. et al: Assessment of the efficacy of buspirone in patients affected by generalized anxiety disorder. randomized. Krebs MO. 2005 [PubMed] Delle Chiaie R. et al: Low level of dopaminergic D2 receptor binding in obsessive-compulsive disorder. van Megen HJ. Am J Psychiatry 154:271–273. Rickels K. Am J Psychiatry 154:1576–1581. 1995 Delorme R. Franke P. et al: Posttraumatic stress disorder in a community group of former prisoners of war: a normative response to severe trauma. double-blind study. Cosgrove GR. 2000 [PubMed] Denys D. Spence SH: The relative efficacy and treatment distress of EMDR and a cognitive-behavior trauma treatment protocol in the amelioration of posttraumatic stress disorder. Christopher NC. Beer DA. et al: A double-blind switch study of paroxetine and venlafaxine in obsessivecompulsive disorder. 1990. Phenomenology. Malloy PF: Efficacy of buspirone in the treatment of posttraumatic stress disorder: an open trial. 1999 [PubMed] DeWit DJ. J Clin Psychopharmacol 15:12–19. 1997 [Full Text] [PubMed] . Chabane N. 1991 Engdahl B. Biol Psychiatry 55:1041–1045. Pancheri P. analytic psychotherapy and anxiety management training for generalized anxiety disorder. et al: Gender differences in the effects of family adversity on the risk of onset of DSM-III-R social phobia. et al: Initial urinary epinephrine and cortisol levels predict acute PTSD symptoms in child trauma victims. American Psychiatric Press. 2004b Denys D. 1999 [PubMed] DeWit DJ. et al: Obsessive-compulsive disorder in patients with schizophrenia or schizoaffective disorder. Baer L. shifting to buspirone from prior treatment with lorazepam: a placebo-controlled. et al: Prior benzodiazepine use and buspirone response in the treatment of generalized anxiety disorder. 2002 [Full Text] [PubMed] Duffy JD. Casacchia M. 1998 [PubMed] Deckert J.Deckert J. Offord DR. pp 226–236 Emmanuel NP. 2004a Denys D. Edited by Wolf ME. Perrault ML. Eberly R. in Posttraumatic Stress Disorder: Etiology. Ballenger JC: Treatment of social phobia with bupropion. Syagailo YV. 2000 [PubMed] Eisen JL. J Clin Psychiatry 65:1040–1048. Murphy R. Hum Mol Genet 81:228–234. et al: Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Mosnaim AD. J Clin Psychiatry 61:91–94. Allan T. J Anxiety Disord 13:131–157. van der Wee N. Br J Psychiatry 165:315–323. Behav Brain Res 169:303–311. Washington. Clark DM: A cognitive model of posttraumatic stress disorder. Ogborne A. 2004c Devilly GJ. Rynn M. Lydiard BR. et al: Systematic mutation screening and association study of the A1 and A2a adenosine receptor genes in panic disorder suggest a contribution of the A2a gene to the development of the disease. 2004 [PubMed] DeMartinis N. J Clin Psychiatry 65:37–43. Psychol Med 29:569–582. Pato MT. and Treatment. Ann Clin Psychiatry 6:33–37.

2005 [PubMed] Fitzgerald KD. 1984 Foa EB. Psychol Med 31:891–898. Edited by Flor-Henry P. et al: A comparison of exposure therapy. placebo controlled study. Psychother Psychosom 74:26–30. 2001a Fava GA. et al: Error-related hyperactivity of the anterior cingulated cortex in obsessivecompulsive disorder. Biol Psychiatry 57:287–294. Frigo M. Grandi S. Biol Psychiatry 49:385–388. Arch Gen Psychiatry 55:918–924. Siliprandi F. Petermann F: Frequency. Jewell G. et al: Long term outcome of social phobia treated by exposure. Rapoport JL. 1994 [Full Text] [PubMed] Flor-Henry P: The obsessive-compulsive syndrome. et al: Risperidone augmentation of serotonin reuptake inhibitor treatment of pediatric obsessive compulsive disorder. Rafanelli C. Appollonio I. J Clin Psychopharmacol 26:84–88. comorbidity. in Cerebral Basis of Psychopathology. Dancu CV. Jewell M. Behav Ther 13:499–510. 1990 [PubMed] Fineberg NA. Goodman WK. and psychosocial impairment of specific phobia in adolescents. Grayson JB. Boston. Murphy DL. et al: Treatment of chronic posttraumatic stress disorder in combat veterans with citalopram: an open trial. et al: Biochemical changes during clomipramine treatment of childhood obsessive-compulsive disorder. Greenberg BD. Conradt J. et al: Intravenous clomipramine for obsessive-compulsive disorder refractory to oral clomipramine: a placebo-controlled study. Psychol Med 31:899–905. Rafanelli C. 1983. Sivakumaran T. et al: Deliberate exposure and blocking of obsessive-compulsive rituals: immediate and long-term effects. Campeas R. et al: Sexually dimorphic relationship of a 5 HT2A promoter polymorphism with obsessive compulsive disorder. 1955 [PubMed] Flint AJ: Epidemiology and comorbidity of anxiety disorders in the elderly. J Consult Clin Psychol 67:194–200. Behav Res Ther 43:1543–1558. stress inoculation therapy. Am J Psychiatry 151:640–649. Liebowitz MR. 2006 [PubMed] Enoch MA. John Coright. Am J Psychiatry 152:90–96. 2000 [PubMed] Fairbank TA. pp 301–311 Foa EB. Guglielmo E. 2005 [PubMed] Ferrarese C. 2001 [PubMed] Erzegovesi S. Tawile V. Behav Ther 15:450–472. 2005 [PubMed] Flament MF. 2001b Fava GA. J Clin Child Psychol 29:221–231. Roberts A. Friedman MJ: Effective Treatments for PTSD: Practice Guidelines From the International Society for . 1987 [PubMed] Flescher J: A dualistic viewpoint on anxiety. and their combination for reducing posttraumatic stress disorder in female assault victims. et al: Adding quetiapine to SRI in treatment resistant obsessive compulsive disorder: a randomized controlled treatment study. Wells A: How effective are cognitive and behavioral treatments for obsessive compulsive disorder? A clinical significance analysis. 1999 [PubMed] Foa EB. 1999 [PubMed] Fitzgerald KD. 1982 Fallon BA. Int Clin Psychopharmacol 20:223–226.English BA. Eur Neuropsychopharmacol 15:69–74. Arch Gen Psychiatry 44:219–225. Pallanti S: Recent life events and panic disorder. et al: DSM-IV field trial: obsessive-compulsive disorder. Grandi S. et al: Low dose risperidone augmentation of fluvoxamine treatment in obsessive compulsive disorder: a double blind. 2005 [PubMed] Fisher PL. Hembree EA. Ruini C. Keane TM. J Am Psychoanal Assoc 3:415–446. Kozak MJ. 2005 [PubMed] Essau CA. J Child Adolesc Psychopharmacol 9:115–123. Welsh RC. Keane TM: Flooding for combat-related stress disorders: assessment of anxiety reduction across traumatic memories. Am J Psychiatry 146:622–626. et al: Decreased density of benzodiazepine receptors in lymphocytes of anxious patients: reversal after chronic diazepam treatment. 1998 [PubMed] Faravelli C. Gehrig WJ. Acta Psychiatr Scand 82:169–173. MA. et al: Well-being therapy of generalized anxiety disorder. Rafanelli C. Murphy DL. Steketee G. 1989 [PubMed] Fava GA. Stewart CM. et al: Long-term outcome of panic disorder with agoraphobia treated by exposure. 1995 [Full Text] [PubMed] Foa EB.

1955. Appel L. Hembree EA. pp 85–117 Freud S: Analysis of a phobia in a five-year-old boy (1909). Translated and edited by Strachey J. 2006 [PubMed] Fux M. 2000 Foa E. London. et al: Cerebral blood flow changes after treatment of social phobia with the neurokinin 1 antagonist GR205171. Vol 12. 2005a Foa EB.Traumatic Stress Studies. J Consult Clin Psychol 73:953–962. Cashman L. et al: Randomized trial of prolonged exposure for posttraumatic stress disorder with and without cognitive restructuring: outcome at academic and community clinics. Hogarth. Michaelovsky E. pp 311–326 Freud S: Introduction to Psychoanalysis and the War Neuroses (1919). 1958. Guilford. England. clomipramine. Vol 20. 1959. Biol Psychiatry 44:1295–1304. et al: Common changes in cerebral blood flow in patients with social phobia treated with citalopram or cognitive behavioral therapy. in The Standard Edition of the Complete Psychological Works of Sigmund Freud. Vol 10. 2005 [PubMed] Furukawa TA. J Am Acad Child Adolesc Psychiatry 37:412–419. London. London. in The Standard Edition of the Complete Psychological Works of Sigmund Freud. 2005b Frank JB. Benjamin J. 1962. Hogarth. 1993 [PubMed] Friedman SD. Neurosci Lett 362:189–192. Watanabe N. Biol Psychiatry 58:132–142. 2000 [PubMed] Furmark T. Psychiatr Genet 16:59–65. J Psychiatr Res 38:323–325. 2004 [PubMed] Fyer AJ: Current approaches to etiology and pathophysiology of specific phobia. New York. Kosten TR. pp 75–175 Frisch A. Arch Gen Psychiatry 59:425–433. pp 69–84 Freud S: On the grounds for detaching a particular syndrome from neurasthenia under the description anxiety neurosis (1895b[1894]). Giller EL Jr. Kozak MJ. Poyurovsky M. England. citalopram or placebo. Vol 3. et al: Brain pH response to hypoventilation in panic disorder: preliminary evidence for altered acid-base regulation. Churchill R: Psychotherapy plus antidepressant for panic disorder with and without agoraphobia: systematic review. London. Vol 3. placebo controlled trial of exposure and ritual prevention. et al: Association between obsessive-compulsive disorder and polymorphisms of genes encoding components of the serotonergic and dopaminergic pathways. Psychophysiology 30:126–130. Br J Psychiatry 188:305–312. Hogarth. 1998 [PubMed] . Wik G. Marteinsdottir I. London. Domschke K. pp 205–215 Freud S: Inhibitions. Tillfors M. Greitz T. et al: A randomized clinical trial of phenelzine and imipramine for posttraumatic stress disorder. Liebowitz MR. 1955. 2006 Freud S: Obsessions and phobias (1895a[1894]). Hayes C. Hogarth. Translated and edited by Strachey J. symptoms and anxiety (1926). Garpenstrand H. et al: Cognitive-behavioral treatment of pediatric obsessive-compulsive disorder: an open clinical trial. et al: Interaction of serotonergic and noradrenergic gene variants in panic disorder. pp 1–149 Freud S: The disposition to obsessional neurosis: a contribution to the problem of choice of neurosis (1913). Hogarth. England. Translated and edited by Strachey J. Tillfors M. Eur Neuropsychopharmacol 10:205–209. Cahill SP. 1962. Vol 17. in The Standard Edition of the Complete Psychological Works of Sigmund Freud. et al: Regional cerebral blood flow during experimental phobic fear. Rothe C. et al: Randomized. Michelgard A. Translated and edited by Strachey J. and their combination in the treatment of obsessive compulsive disorder. Am J Psychiatry 162:151–161. Mathis CM. 1988 [PubMed] Franklin ME. London. in The Standard Edition of the Complete Psychological Works of Sigmund Freud. Nemets B: A placebo controlled cross over trial of adjunctive EPA in OCD. et al: Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia. Kozak MJ. England. 1998 [PubMed] Fredrikson M. in The Standard Edition of the Complete Psychological Works of Sigmund Freud. Hogarth. Am J Psychiatry 145:1289–1291. 2004 [PubMed] Furmark T. England. in The Standard Edition of the Complete Psychological Works of Sigmund Freud. Translated and edited by Strachey J. 2006 [Full Text] [PubMed] Freitlag CM. Translated and edited by Strachey J. Am J Psychiatry 163:710–715. 2002 [PubMed] Furmark T.

Stein MB. Moore GJ. Arch Gen Psychiatry 57:449–456. Behav Res Ther 40:983–993. Am J Psychiatry 161:2186–2193. et al: Efficacy of venlafaxine extended-release capsules in nondepressed outpatients with generalized anxiety disorder: a 6-month randomized controlled trial. 2002 [PubMed] Gelenberg AJ. et al: Impaired GABA neuronal response to acute benzodiazepine administration in panic disorder.Fyer AJ. et al: Familial aggregation and phenomenology of "early" onset (at or before age 20 years) panic disorder. Biol Psychiatry 32:457–461. Page GP. Cimbolic P. Ekhator NN. Southwick S. American Psychiatric Press. 2000 [PubMed] Gelernter CS. Arch Gen Psychiatry 58:556–561. Bonvicini K. Am J Psychiatry 161:59–66. Gallops MS. open label study. 2000 [Full Text] [PubMed] Gilbert AR. placebo controlled trial. 1992 [PubMed] Giedd JN. Washington. Rapoport JL. 2003 [PubMed] Gelernter J. Page G. Rudolph RL. et al: Reductions in occipital cortex GABA levels in panic disorder detected with 1H-magnetic resonance spectroscopy. Almai A. Am J Med Genet 105:548–557. Arch Gen Psychiatry 58:681–686. De-Berardis D. Lydiard RB. Garvey MA. 2004 [Full Text] [PubMed] Geller DA. et al: Mirtazapine treatment of generalized anxiety disorder: a fixed dose. Am J Psychiatry 160:1919–1928. DC. et al: Beyond the serotonin hypothesis: a role for dopamine in some forms of . Woods SW: Genome-wide linkage scan for loci predisposing to social phobia: evidence for a chromosome 16 risk locus. 1991 [PubMed] Gelernter J. Page GP. Almai A. Am J Psychiatry 157:281–283. et al: A chromosome 24 risk locus for simple phobia: results from a genomewide linkage scan. et al: Early coadministration of clonazepam with sertraline for panic disorder. Am J Psychiatry 163:637–643. 1990 [PubMed] Gabbard GO: Psychodynamic Psychiatry in Clinical Practice. Keshavan MS. Am J Psychiatry 158:1227–1230. Horwath E. 1990 Gambi F. et al: Cognitive-behavioral and pharmacological treatments of social phobia: a controlled study. et al: Decrease in thalamic volumes of pediatric patients with obsessivecompulsive disorder who are taking paroxetine. 2004 [PubMed] Geracioti TD Jr. 1997 [PubMed] Goodman WK. et al: Anger and anxiety responses to m-chlorophenylpiperazine in generalized anxiety disorder. J Am Acad Child Adolesc Psychiatr 43:1387–1396. Baker DG. multicenter. JAMA 283:3082–3088. 2001 [PubMed] Gelernter J. Emslie G. Arch Gen Psychiatry 54:271–278. Campanella D. Woods SW. Klein DF: Controlled imipramine treatment of school phobia. Stewart SE. 2001b Goddard AW. Price LH. Mannuzza S. 2003 [Full Text] [PubMed] Geller DA. 1971 Goddard AW. Appel M. et al: Linkage genome scan for loci predisposing to panic disorder or agoraphobia. 2006 [Full Text] [PubMed] Germine M. Hoffman H. Biederman J. et al: No association between D2 dopamine receptor (DRD2) "A" system alleles or DRD2 haplotypes and posttraumatic stress disorder. Uhde TW. Wagner KD. J Psychopharmacol 19:483–487. 2001a Goddard AW. 2004 [Full Text] [PubMed] Goldstein RB. McDougle CJ. Mason GF. double blind. Carpenter LL. Mason GF. 2001 [Full Text] [PubMed] Geracioti TD. 1999 [PubMed] Gelernter J. et al: Elevated cerebrospinal fluid substance P concentrations in posttraumatic stress disorder and major depression. Carlin A. 2005 [PubMed] Garcia-Palacios A. Arch Gen Psychiatry 25:204–207. Mol Psychiatry 8:71–82. et al: Paroxetine treatment in children and adolescents with obsessive compulsive disorder: a randomized. et al: CSF norepinephrine concentrations in posttraumatic stress disorder. Arch Gen Psychiatry 47:252–256. Goodson S. Brouette T. Owens MJ. Bonvicini K. Biol Psychiatry 45:620–625. 2000 [PubMed] Gittelman-Klein R. Wickramaratne PJ. et al: Familial transmission of simple phobias and fears: a preliminary report. Arch Gen Psychiatry 48:938–945. et al: MRI assessment of children with obsessive-compulsive disorder or tics associated with streptococcal infection. et al: Virtual reality in the treatment of spider phobia: a controlled study. Goddard AW. et al: Which SSRA? A meta analysis of pharmacotherapy trials in pediatric obsessive compulsive disorder.

et al: Double-blind study of adjuvant buspirone for fluoxetine-treated patients with obsessive-compulsive disorder. J Clin Psychiatry 67:363–374. Am J Psychiatry 141:857–861. J Abnorm Psychol 108:134–142. Arch Gen Psychiatry 52:289–295. placebo-controlled trials. 1985 [PubMed] Gorman JM. J Affect Discord 87:161–167. 1995a Greist JH. Stinson FS. et al: Effect of imipramine on prolapsed mitral valves of patients with panic disorder. Fyer MR. Compr Psychiatry 39:160–164. revised. Bathurst E. Am J Psychiatry 150:819–821. Popli A. 2005a Grant BF. Fyer AJ. et al: Ventilatory physiology of patients with panic disorder. 2000 [PubMed] adrenergic blockade on lactate-induced panic. 2005 [PubMed] Gorman JM. Horwood LJ: Childhood abuse and familial violence and the risk of panic attacks and panic disorder in young adulthood. 1984 [PubMed] Gorman JM. Levy GF. Lasko NB. Stinson FS. 1998 [PubMed] Gupta S. correlates. Pigott TA. L'Heureux F. et al: Neurologic soft signs in chronic posttraumatic stress disorder. 1990 Goodman WK. 1998 [PubMed] Gurvits TV. Am J Psychiatry 142:864–866. Cohen H. et al: Effect of acute Psychiatry 40:1079–1082. Kobak KA. Askanazi J. Amir M. Blanco C. 1995b Greist JH. Kent JM. Battista D. 1981 [PubMed] Gorman JM. 1989 [PubMed] Gorman JM. 1993 [Full Text] [PubMed] Grant BF. 2005 [PubMed] Goodwin RD. Goetz RR. Hasin DS. et al: Response to hyperventilation in a group of patients with panic disorder. Bose A. Coplan JD. et al: The effect of successful treatment on the emotional and physiological response to carbon dioxide inhalation in patients with panic disorder. et al: The epidemiology of social anxiety disorder in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. 1999 [PubMed] Grisaru N. et al: Neuroanatomical hypothesis of panic disorder. 1995c Grillon C. Fergusson DM. Biol Psychiatry 56:862–867. Psychol Med 35:881–890. Am J Psychiatry 157:493–505. 1983 [PubMed] Gorman JM. Arch Gen Psychiatry 57:181–186. et al: Effect of transcranial magnetic stimulation in posttraumatic stress disorder: a preliminary study. et al: A comparison of sodium bicarbonate and sodium lactate infusion in the induction of panic attacks. 2004 [PubMed] Grady TA. Arch Gen Psychiatry 52:53–60. Gliklich J. et al: Double-blind parallel comparison of three dosages of sertraline and placebo in outpatients with obsessive-compulsive disorder. Martinez J. et al: Efficacy of cyproheptadine for nightmares associated with posttraumatic stress disorder. Liebowitz MR. DuBoff E. Hasin DS. et al: The epidemiology of DSM-IV panic disorder and agoraphobia in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Fyer AF. Morgan CA: Fear-potentiated startle conditioning to explicit and contextual cues in Gulf War veterans with posttraumatic stress disorder. Int Clin Psychopharmacol 10:57–65. et al: Lactate infusions in obsessive-compulsive disorder. Chouinard G. 2006 [PubMed] Greist JH. Goetz R. Biol Psychiatry 44:52–55. and comparative disability of DSM-IV generalized anxiety disorder in the USA: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen . et al: Efficacy and tolerability of serotonin transport inhibitors in obsessivecompulsive disorder: a meta-analysis. Wang Q: Treatment of generalized anxiety disorder with escitalopram: pooled results from double-blind. Liebowitz MR. Am J Psychiatry 138:977–978. et al: Prevalence. 2005b Grant BF. Gilbertson MW. Kobak KA. Liebowitz MR. Sullivan GM. Psychol Med 35:1747–1759. comorbidity. Hasin DS. Jefferson JW. Arch Gen Psychiatry 46:145–150. 1988 [PubMed] Gorman JM. Arch Gen Psychiatry 45:31–39. et al: A 1-year double-blind placebo-controlled fixed dose study of sertraline in the treatment of obsessive-compulsive disorder. J Clin Psychiatry 66:1351–1361. 2000 [Full Text] [PubMed] Gorman JM. Jefferson JW.obsessive compulsive disorder? J Clin Psychiatry 51 (suppl):36–43.

Biol Psychiatry 45:615–619. Hellstrom K. Dodge CS. et al: No coding variant of the tryptophan hydroxylase gene detected in seasonal affective disorder. Biol Psychiatry 45:1226–1229. Brodrick PS. Iancu I. 2000 [PubMed] . Butterfield MI. Hope DA. Nielsen DA. 2003 [PubMed] Hamilton SP. Behav Res Ther 44:657–665. et al: Evidence for a susceptibility locus for panic disorder near the catecholO-methyltransferase gene on chromosome 22. DeLeon AB. et al: Exposure therapy and sertraline in social phobia: 1-year follow up of a randomized controlled trial. et al: One-year follow-up of pharmacotherapy-resistant patients with panic disorder treated with cognitive-behavior therapy: outcome and predictors of remission. Heiman GA. van der Kolk BA: Traumatic antecedents of borderline personality disorder. Am J Psychiatry 146:490–495. Draemer HC. et al: Cognitive behavioral group therapy vs phenelzine therapy for social phobia: a 12-week outcome. et al: A susceptibility gene for affective disorders and the response of the human amygdala. Arch Gen Psychiatry 62:146–152. obsessive-compulsive disorder. American Psychiatric Press. placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 37:1308–1316. Am J Psychiatry 157:626–628. Am J Med Genet 114:541–552. clonazepam. Rosenthal NE. Arch Gen Psychiatry 63:571–576. and alcoholism. J Clin Psychopharmacol 20:556–559.Gurvits TV. van der Kolk BA: Childhood trauma in borderline personality disorder. 2006 [PubMed] Hamilton SP. et al: Quetiapine treatment in patients with posttraumatic stress disorder: an open trial of adjunctive therapy. 1999 [PubMed] Hanna GL. 2004 [PubMed] Hamner MB. 2002 [PubMed] Hamilton SP. et al: Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q. pp 111–126 Herman JL. 1990b Heimberg RG. et al: Genome wide linkage analysis of families with obsessive compulsive disorder ascertained through pediatric probands. 2000 [Full Text] [PubMed] Haug TT. anorexia nervosa. 2004 [Full Text] [PubMed] Hewlett WA. and clonidine treatment of obsessive-compulsive disorder. Proc Natl Acad Sci USA 100:2550–2555. et al: Subtle neurologic compromise as vulnerability factor for combat related posttraumatic stress disorder: results of a twin study. 2002 [PubMed] Hariri AR. et al: Cognitive behavioral group treatment for social phobia: comparison with a credible placebo control. 2003 [PubMed] Han L. DC. et al: Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder. et al: Linking self-reported childhood behavioral inhibition to adolescent social phobia. J Nerv Ment Dis 178:172–179. Feldman ME. Hope DA. Fyer AJ. Lasko NB. Slager SL. 1999 [PubMed] Hettema JM. Slager SL. 1989 [PubMed] Hertzberg MA. Hope DA. Agras WS: Clomipramine. Neuropsychopharmacol 29:558–565. Arch Gen Psychiatry 55:1133–1141. Dodge CS. Vinogradov S. Bryant RA: Two-year prospective evaluation of the relationship between acute stress disorder and posttraumatic stress disorder following mild traumatic brain injury. Edited by van der Kolk BA. Kipper L. 2005 [PubMed] Harvey AG. 1998 [PubMed] Heldt E. Gus-Manfro G. Metzger LJ. Blomhoff S. 2003 [PubMed] Hayward C. Perry JC. Liebowitz MR. Veenstra VanderWeele J. Br J Psychiatry 182:312–318. Am J Psychiatry 161:1581–1587. Cognit Ther Res 14:1–23. Durner M. in Psychological Trauma. J Clin Psychopharmacol 23:15–20. Killen JD. et al: Pindolol augmentation in patients with treatment-resistant panic disorder: a double-blind. Kendler KS: Genetic and environmental sources of covariation between generalized anxiety disorder and neuroticism. 1990a Heimberg RG. et al: A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder. Prescott CA. Munoz KE. Deitsch SE. Dannon PN. et al: DSM-III-R subtypes of social phobia: comparison of generalized social phobics and public speaking phobics. Drabant EM. 2006 [PubMed] Herman JL. Washington. Cox NJ. Biol Psychiatry 51:591–601. J Clin Psychopharmacol 12:420–430. 1998 [PubMed] Heimberg RG. 1987. 1992 [PubMed] Hirschmann S.

et al: Venlafaxine in treatment resistant obsessive compulsive disorder. Lipsky RH. Italy. Psychiatry Res 79:213–217. J Clin Psychiatry 64:640–647. Hochrein A. placebo controlled study of the efficacy and safety of controlled release fluvoxamine in patients with obsessive compulsive disorder. Nitescu A. et al: Cortisol and sodium lactate-induced panic. 2005 [PubMed] Hofmann SG. Int J Neuropsychopharmacol 6:397–401. Kwon J. Br J Psychiatry 167:76–79. et al: Serotonin transporter promoter gain of function genotypes are linked to obsessive compulsive disorder. Biol Psychiatry 57:1153–1158. 2003a Hollander E. et al: Potential effectiveness and safety of olanzapine in refractory panic disorder. Bienstock C. Wilner N. J Consult Clin Psychol 72:588–596. 2004 [PubMed] Hofmann SG. Hazlett RL. 1991b Hollander E. 1988 [PubMed] Hoehn-Saric R. DeCaria C. 2006 [PubMed] Hudson J. et al: Noradrenergic function in obsessive-compulsive disorder: behavioral and neuroendocrine responses to clonidine and comparison to healthy controls. Gorman JM. 1998 [PubMed] Hollander E. 2006 [PubMed] Hollander E. Zhu G. Zimmerli WD: Differential effects of alprazolam and imipramine in generalized anxiety disorder: somatic versus psychic symptoms. 2005 [PubMed] Hofmann SG: Perception of control over anxiety mediates the relation between catastrophic thinking and social anxiety in social phobia. 1980 Hu XZ. et al: The International Treatment Refractory OCD Consortium: preliminary findings. Thompson PM. McLeod DR: Generalized anxiety disorder with early and late onset of anxiety symptoms. et al: Serotonergic function in obsessive-compulsive disorder: behavioral and neuroendocrine responses to oral m-chlorophenylpiperazine and fenfluramine in patients and healthy volunteers. et al: Risperidone augmentation in treatment resistant obsessive compulsive disorder: a double blind. Am J Hum Genet 78:815–826. et al: Signs and symptoms of posttraumatic stress disorders. Quednow BB. J Clin Psychiatry 64:546–550. Kim HJ. Friedberg J. McLeod DR. Gully R. Ruiz JE. Sood E. Pallanti S. 1992 [PubMed] Hollander E. Sardinia. 1976 Horowitz MJ. Arch Gen Psychiatry 38:440–445. J Clin Psychiatry 49:293–301. Compr Psychiatry 34:291–298. Kaltreider N. 1993 [PubMed] Hoenig K. Liebowitz MR. 2006 [PubMed] Hogben GL. McNally RJ: Panic disorder and suicide attempt: a reanalysis of data from the Epidemiologic Catchment Area study. 2000 [PubMed] . Arch Gen Psychiatry 49:21–28. Weiller F. Int Clin Psychopharmacol 21:189–191. Arch Gen Psychiatry 37:88–92. 1991a Hollander E.Hoehn-Saric R. Nitescu A. placebo controlled study. DeCaria CM. New York. et al: Impaired prepulse inhibition of acoustic startle in obsessive compulsive disorder. Arch Gen Psychiatry 46:135–140. Arch Gen Psychiatry 63:298–304. 2003b Hollander E. Dell'Osso B: Topiramate plus paroxetine in treatment resistant obsessive compulsive disorder. Psychiatry Res 36:1–17. et al: Effects of chronic fluoxetine treatment on behavioral and neuroendocrine responses to meta-chlorophenylpiperazine in obsessive-compulsive disorder. Presented at the 5th International OCD Conference. Koran LM. DeCaria C. 1989 [PubMed] Hollander E. March 2001 Hollander E. Baldini Rossi N. Meuret AE. 2003c Hollifield M. Smits JA. 2005 [PubMed] Hornig CD. et al: Serotonergic function in social phobia: comparison to normal control and obsessive-compulsive disorder subjects. et al: Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Cornfield RB: Treatment of traumatic war neurosis with phenelzine. Moscovitch DA. Behav Res Ther 43:885–895. et al: Changes in self perception during treatment of social phobia. Depress Anxiety 21:33–40. 1981 [PubMed] Hollander E. Rapee R: The origins of social phobia. Goodman WK. Psychiatry Res 37:161–177. 1995 [PubMed] Horowitz MJ: Stress-Response Syndromes. Behav Modif 24:102–129. Jason Aronson. Wasserman D. et al: A double blind.

et al: Self-exposure therapy for panic disorder with agoraphobia: randomized controlled study of external v. and suicide attempts. et al: Metyrapone tests in patients with panic disorder. Altemus M. Bailliere. Greist JH. et al: Family based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. 2002 [PubMed] Karayiorgou M. comorbidity. Weissman MM. Hoogduin CA. flexible dosage study. placebo-controlled crossover study. 1997 [Full Text] [PubMed] Johanson A. Lydiard R. Sobin C. Taylor VE. 1908 Jenike MA. 1995 [Full Text] [PubMed] Keck PE. 1997 [PubMed] Karayiorgou M. et al: Plasma and CSF HVA levels in panic patients with comorbid social phobia. et al: A randomized. 1987 [PubMed] Kampman M. et al: The epidemiology of obsessive-compulsive disorder in five US communities. Galke BL. et al: Changes in frontal lobe activity with cognitive therapy for spider phobia. Vol 201. Biol Psychiatry 56:898–900.Inada Y. Hoogduin CA. 1990 [PubMed] Johnson M. Amering M. Brawman MO. Am J Psychiatry 154:1261–1264. et al: Abnormal benzodiazepine receptor density associated with generalized social phobia. et al: Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. 2nd Edition. Biol Psychiatry 36:425–427. J Nerv Ment Dis 181:539–544. placebo controlled. 1994 [PubMed] Johnson MR. interoceptive self-exposure. et al: Positive association between panic disorder and polymorphism of the serotonin 2A receptor gene. Reznick JS. Baer L. Hyman S. Arch Gen Psychiatry 48:548–555. 1998 [PubMed] Kagan J. 1999 [PubMed] Kardiner A: Traumatic neurosis of war. placebo-controlled study of the effects of adjunctive paroxetine in panic disorder patients unsuccessfully treated with cognitive-behavioral therapy alone. 1990 [PubMed] Jenike MA. Yassouridis A. 2001 [PubMed] Janet P: Les Obsessions et la Psychasthenie. 1993 [PubMed] Keijsers GP. Marazziti D. 1994 [PubMed] Kellner M. et al: Sertraline for social phobia: a double-blind. 1988 [PubMed] Kasper S. Arch Gen Psychiatry 45:1094–1099. . Schick M. Proc Natl Acad Sci USA 94:4572–4575. et al: Valproate treatment of panic disorder and lactate-induced panic attacks. Yoneda H. Risberg J. Zealberg J. Kobak KA. Am J Psychiatry 152:1368–1371. double-blind. Biol Psychiatry 45:1178–1189. 1995 [PubMed] Katzelnick DJ. et al: Long-term follow-up after a drug trial for panic disorder. deAraujo LA. 1959. Tess VL. Br J Psychiatry 178:331–336. 2006 [PubMed] Johnson J. Psychiatry Res 118:25–31. Br J Psychiatry 167:487–494. 2005 Katerndahl DA: Panic and prolapse: meta-analysis. Sorenson SB. Appl Neuropsychol 13:34–41. Baer L. Br J Psychiatry 165:781–786. Minichiello WE. Klerman GL: Panic disorder. Keijers GP. Edited by Arieti S. pp 245–257 Karno M. et al: Placebo-controlled trial of fluoxetine and phenelzine for obsessive-compulsive disorder. in American Handbook of Psychiatry. 2003 [PubMed] Ito LM. Tucker DM. Am J Psychiatry 147:1209–1215. Bludell ML. Paris. J Clin Psychiatry 63:772–777. Schaap CP: Predictors of treatment outcome in the behavioral treatment of obsessivecompulsive disorder. France. Stolk JM. Koh J. 1993 [PubMed] Katschnig H. Arch Gen Psychiatry 47:805–808. 1991 [PubMed] Jenike MA. Tugrul KC. Ballantine HT. Biol Psychiatry 43:306–309. Stein DJ. Biol Psychiatry 33:542–546. Snidman N: The physiology and psychology of behavioral inhibition in children. Loft H. New York. Basic Books. Baer L. et al: Escitalopram in the treatment of social anxiety disorder: randomized. et al: A controlled trial of fluvoxamine in obsessive-compulsive disorder: implications for a serotonergic theory. Br J Psychiatry 186:22–26. Golding JM. Child Dev 58:1459–1473. et al: Cingulotomy for refractory obsessive-compulsive disorder: a long-term follow-up of 33 patients.

Am J Psychiatry 156:1915–1923. in Anxiety: New Research and Changing Concepts. Vaccarino C. Mawlawi O. Am J Med Genet . J Clin Psychiatry 67:211–214. Bromet E. et al: Generalized anxiety disorder in women: a population-based twin study. et al: Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta analysis. Bouchard S. Cyberpsychol Behav 8:76–88. et al: Rethinking the duration requirement for generalized anxiety disorder: evidence from the National Comorbidity Survey Replication. et al: Prediction of panic response to a respiratory stimulant by reduced orbitofrontal cerebral blood flow in panic disorder. et al: Specificity of panic response to CO(2) inhalation in panic disorder: a comparison with major depression and premenstrual dysphoric disorder. 2005 [PubMed] Kessler RC. Hanna GL. 2005 [Full Text] [PubMed] Kenwright M. Psychopharmacologia 5:397–408. Kessler RC. J Nerv Ment Dis 177:546–550. Am J Psychiatry 162:1379–1381. et al: Results of a genome-wide genetic screen for panic disorder. Edited by Klein DF. Am J Psychiatry 158:58–67. spontaneous panics. Psychol Med 35:1073–1082. and related conditions: an integrative hypothesis. Papp LA. 2004 [PubMed] Kessler RC. et al: Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the National Comorbidity Survey. Lee MC. 1994 [PubMed] Kessler RC. Vieland VJ. Marks IM: Computer aided self help for phobia/panic via internet at home: a pilot study. 2000 [PubMed] Kinrys G. Raven. Koszycki D. et al: Grey matter abnormalities in obsessive compulsive disorder: statistical parametric mapping of segmented magnetic resonance images. Psychol Med 29:555–567. 1999 [PubMed] Kent JM. Arch Gen Psychiatry 50:306–317. 2005 [PubMed] Klein DF: Delineation of two drug responsive anxiety syndromes. Zhao S. 1989 [PubMed] Kitayama N. 1993 [PubMed] Klein M: A contribution to the theory of anxiety and guilt. Arch Gen Psychiatry 51:8–19. 1999b Kessler RC. Rabkin JG. Kim J. et al: Virtual reality therapy versus cognitive behavior therapy for social phobia: a preliminary controlled study. Int J Psychoanal 29:114–123. Stang P. 1964 [PubMed] Klein DF: Anxiety reconceptualized. Am J Psychiatry 139:364–365. 1999a Kessler RC.2004 [PubMed] Kendler KS. Arch Gen Psychiatry 63:415–424. et al: Levetiracetam for treatment-refractory posttraumatic stress disorder. 2006 [PubMed] Kim JJ. Leung P: Clonidine in Cambodian patients with posttraumatic stress disorder. Brandenburg N. et al: Posttraumatic stress disorder in the National Comorbidity Survey. 1981. Jin R. 2001 [PubMed] Kim SJ. et al: Mutation screening of human 5HT(2B)receptor gene in early onset obsessive-compulsive disorder. Mol Psychiatry 4:284–285. Pardo TB. Bradwejn J. and agoraphobia in the National Comorbidity Survey Replication. Chiu WT. 1992 [PubMed] Kennedy JL. Neale MC. McGonagle KA. et al: Investigation of cholecystokinin system genes in panic disorder. Legeron P. Lane M. 2001 [Full Text] [PubMed] Kent JM. et al: The epidemiology of panic attacks. Br J Psychiatry 184:448–449. pp 235–263 Klein DF: False suffocation alarms. Kutner M. DuPont RL. Br J Psychiatry 179:330–334. New York. et al: Lifetime comorbidities between social phobia and mood disorders in the US National Comorbidity Survey. Sonnega A. 1948 Klinger E. Wygant LE. Berglund P. panic disorder. Arch Gen Psychiatry 52:1048–1060. 1982 [PubMed] Knowles JA. et al: Impairment in pure and comorbid generalized anxiety disorder and major depression at 12 months in two national surveys. Martinez JM. Arch Gen Psychiatry 49:267–272. 2006 [PubMed] Kinzie JD. Mol Cell Probes 14:47–52. Coplan JD. 1995 [PubMed] Kessler RC. Veenstra-VanderWeele J. Fyer AJ. J Affect Disord 88:79–86. 2005 [PubMed] Knesevich JW: Successful treatment of obsessive-compulsive disorder with clonidine hydrochloride. Wittchen HU.

et al: Risperidone in psychotic combat related posttraumatic stress disorder: an open label trial. 2006 [PubMed] Koren D. Ward H. Edited by van der Kolk BA. 1997 [Full Text] [PubMed] Lee C. et al: Functional connectivity of dissociative responses in posttraumatic stress disorder: a functional magnetic resonance imaging investigation. follow-up study. 1987 [PubMed] Kolb LC. pp 97–105 Koran LM. Boardman J. Hollifield M. Psychopharmacology (Berl) 136:205–216. Lenane MC. et al: St. 2005b Kolb LC: A neuropsychological hypothesis explaining posttraumatic stress disorders. 1993 [PubMed] Lepola UM. J Clin Psychiatry 59:528–534. Muck Seler D.28:139–147. Washington. Sheikh JI: Lifetime trauma history and panic disorder: findings from the National Comorbidity 7-year follow-up study of 54 obsessive compulsive children and adolescents. 2005 [PubMed] Koran LM. et al: Imagery rehearsal therapy for chronic nightmares in sexual assault survivors with posttraumatic stress disorder: a randomized controlled trial. 2002 [PubMed] Levin P. et al: Mirtazapine for obsessive compulsive disorder: an open trial followed by double blind discontinuation. Pivac N. 1994 [PubMed] Leckman JF. Apter J. 1998 [PubMed] Kobak KA. et al: Elevated cerebrospinal fluid levels of oxytocin in obsessive-compulsive disorder: comparison with Tourette's syndrome and healthy controls. Warner G. 1999 [PubMed] Krystal H: Massive Psychic Trauma. International Universities Press. et al: St. Am J Psychiatry 156:367–373. Taylor LV. et al: Symptoms of obsessive-compulsive disorder. Burris BC. John's wort versus placebo in social phobia: results from a placebo controlled pilot study. Biol Psychiatry 57:873–884. J Clin Psychiatry 66:515–520. Kelmendi B. 1-year trial of citalopram in the treatment of panic disorder. multicenter study of sertraline treatment for obsessivecompulsive disorder. et al: A controlled. J Clin Psychiatry 66:922–927. Griffiths S: Propranolol and clonidine in treatment of the chronic post-traumatic stress disorders of war. Jefferson JW. 2005a Kobak KA. North WG. J Anxiety Disord 16:599–603. J Clin Psychopharmacol 26:79–83. Arch Gen Psychiatry 51:782–792. Arch Gen Psychiatry 50:429–439. Goodman WK. et al: Pulse loaded intravenous clomipramine in treatment resistant obsessive compulsive disorder. Arnon I. Gavriel H. prospective. John's wort versus placebo in obsessive compulsive disorder: results from a double blind study. in Post-Traumatic Stress Disorder: Psychological and Biological Sequelae. J Clin Psychopharmacol 25:51–58. van der Kolk B: What psychological testing and neuroimaging tell us about the treatment of posttraumatic stress disorder by eye movement desensitization and reprocessing. 1968 Lafleur DL. Pittenger C. Taylor LV. Am J Psychiatry 154:911–917. 2005 Leonard HL. Int Clin Psychopharmacol 20:299–304. 1998 Kobak KA. Gamel NN. Klein E: Acute stress response and posttraumatic stress disorder in traffic accident victims: a one-year prospective. Am J Psychiatry 144:989–995. Depress Anxiety 21:1135–1139. 1999 . J Clin Psychopharmacol 19:172–176. J Anxiety Disord 13:159–172. American Psychiatric Press. Psychopharmacology 284:254–256. Leinonen EV. Johnston L. Asnis G. Wade AG. Swedo SE. 2005 [PubMed] Leckman JF. Greist JH. Grice DE. Aboujaoude E. Williamson PC. 1999 [Full Text] [PubMed] Kozaric-Kovacic D. Drummond P. 1998 [PubMed] Leskin GA. et al: N acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive compulsive disorder. Kang RH. Bluhm RL. et al: Placebo-controlled. Lee MS. New York. et al: Treatment of PTSD: stress inoculation training with prolonged exposure compared to EMDR. et al: A 2. 2005 [PubMed] Krakow B. Bystritsky A. JAMA 286:537–545. Choung HW. et al: Influence of serotonin transporter promoter gene polymorphism on susceptibility to posttraumatic stress disorder. 2001 [PubMed] Kronig MH. DC. 2002 [PubMed] Lee HJ. Lazrove S. 2006 Lanius RA. J Clin Psychol 58:1071–1089. et al: Behavioral versus pharmacological treatments of obsessive compulsive disorder: a meta-analysis. 1984.

2005 [PubMed] Lindley SEE. Psychosomatics 27:849–854. et al: Risperidone and haloperidol augmentation of serotonin reuptake inhibitors in refractory obsessive compulsive disorder: a crossover study. Schneier F. Am J Psychiatry 156:1814–1816. et al: Cognitive-behavioral therapy versus phenelzine in social phobia: long-term outcome. Heimberg RG. in Post-Traumatic Stress Disorder: Psychological and Biological Sequelae. 2003 [PubMed] Liebowitz MR. De Martinis NA. Schneier FR. Tolbert LC. Piacentini J. et al: Lactate provocation of panic attacks. Arch Gen Psychiatry 49:290–300. Vlieger EJ. Kinnear CJ. May RS. Depress Anxiety 10:105–111. Depress Anxiety 10:89–98. Mannuzza S. 2002b Liebowitz MR. parenting styles. American Psychiatric Press. Meyerson BA. 1999 [PubMed] Lipschitz DS. J Am Acad Child Adolesc Psychiatry 44:807–814. J Clin Psychiatry 66:1155–1160. et al: Preliminary study of carbamazepine in post-traumatic stress disorder. Neurosurgery 44:452–458. et al: Hoarding in obsessive compulsive disorder: clinical and genetic correlates. Grady TA. and the risk of social phobia in offspring: a prospective-longitudinal community study. et al: Social phobia: review of a neglected anxiety disorder. et al: Phenelzine vs atenolol in social phobia: a placebo-controlled comparison. Arch Gen Psychiatry 62:190–198. II: biochemical and physiological findings. Hofler M. Edited by van der Kolk BA. Jalink M. 1985a Liebowitz MR. 2005 [PubMed] . Gorman JM. Gorman JM. 1999 [PubMed] Liebowitz MR. Carlson EB. placebo controlled study. 2005 [PubMed] Lieb R. Green BL: Building a conceptual bridge between civilian trauma and war trauma: preliminary psychological findings from a clinical sample of Vietnam veterans. Mayes LM. Fyer AJ. et al: Lesion topography and outcome after thermocapsulotomy or gamma knife capsulotomy for obsessive-compulsive disorder: relevance of the right hemisphere. double blind. 1999b Lochner C. Grace MC. J Trauma Stress 18:205–212. Gelenberf AJ. placebo and paroxetine in social anxiety disorder. et al: Fluoxetine in children and adolescents with OCD: a placebo controlled trial. 2002a Liebowitz MR. Campeas R. Weihs K. 1985b Liebowitz MR. Turner SM. Cherry S. et al: Efficacy of sertraline in severe generalized social anxiety disorder: results of a double blind. Arch Gen Psychiatry 42:709–719. DC. Biol Psychiatry 55:940–945. Wittchen HU. Benoit M: Basal and dexamethasone suppressed salivary cortisol concentration in a community sample of patients with posttraumatic stress disorder. Tancer M. Gersons BP. Klein DF. J Clin Psychiatry 66:736–743. 2004 [PubMed] Lindauer RJ. 1992 [PubMed] Liebowitz MR. 1999a Lipsitz JD. Davidson JRT. Hemmings SM. J Clin Psychiatry 63:66–74. 1984 [PubMed] Liebowitz MR. 1986 [PubMed] Lippitz BE. 2005 [PubMed] Lindauer RJ. vanMeijel EP. et al: Open trial of interpersonal psychotherapy for the treatment of social phobia. Mindus P. et al: A randomized. Arch Gen Psychiatry 42:729–736. Washington. fixed dose comparison of paroxetine and placebo in the treatment of generalized social anxiety disorder. et al: Specific phobia 10–16 years after treatment. et al: Effects of brief eclectic psychotherapy in patients with posttraumatic stress disorder: randomized clinical trial. 2005 [PubMed] Lipsitz JD. Gorman JM. et al: Smaller hippocampal volume in Dutch police officers with posttraumatic stress disorder. Markowitz JC. 2005 Lindy JD. Arch Gen Psychiatry 41:764–770. I: clinical and behavioral findings. et al: Baseline and modulated acoustic startle responses in adolescent girls with posttraumatic stress disorder. J Clin Psychiatry 64:785–792. et al: Parental psychopathology. J Am Acad Child Adolesc Psychiatry 41:1431–1438. Arch Gen Psychiatry 57:859–866. 2000 [PubMed] Liebowitz MR. 1984. Fyer AJ.[PubMed] Li X. Biol Psychiatry 56:356–363. Rasmussen AM. et al: Lactate provocation of panic attacks. Stein MB. pp 44–57 Lipper S. Fyer AJ. Munjack D: Venlafaxine extended release vs.

Londborg PD, Wolkow R, Smith WT, et al: Sertraline in the treatment of panic disorder: a multi-site, double-blind, placebo-controlled, fixed-dose investigation. Br J Psychiatry 173:54–60, 1998 [PubMed] Lorberbaum JP, Lose S, Johnson MR, et al: Neural correlates of speech anticipatory anxiety in generalized social phobia. Neuroreport 15:2701–2705, 2004 [PubMed] Lucey JV, Barry S, Webb MG, et al: The desipramine-induced hormone response and the dexamethasone suppression test in obsessive-compulsive disorder. Acta Psychiatr Scand 86:367–370, 1992 [PubMed] MacDonald PA, Antony MM, Macleod CM, et al: Memory and confidence in memory judgements among individuals with obsessive compulsive disorder and nonclinical controls. Behav Res Ther 35:497–505, 1997 [PubMed] Macklin ML, Metzger LJ, Litz BT, et al: Lower precombat intelligence is a risk factor for posttraumatic stress disorder. J Consult Clin Psychol 66:323–326, 1998 [PubMed] Macklin ML, Metzger LJ, Lasko NB, et al: Five-year follow-up study of eye movement desensitization and reprocessing therapy for combat-related posttraumatic stress disorder. Compr Psychiatry 41:24–27, 2000 [PubMed] MacLeod C, Cohen IL: Anxiety and the interpretation of ambiguity: a text comprehension study. J Abnorm Psychol 2:102, 1993 MacLeod C, McLaughlin K: Implicit and explicit memory bias in anxiety: a conceptual replication. Behav Res Ther 33:1–14, 1995 [PubMed] Magee WJ, Eaton WW, Wittchen HU, et al: Agoraphobia, simple phobia, and social phobia in the National Comorbidity Survey. Arch Gen Psychiatry 53:159–168, 1996 [PubMed] Maier SF, Seligman ME: Learned helplessness: theory and evidence. J Exp Psychol 105:3–46, 1976 Maier SF, Dovies S, Gran JW: Opiate antagonists and long-term analgesic reaction induced by inescapable shock in rats. J Comp Physiol Psychol 94:1172–1183, 1980 [PubMed] Maletzky B, McFarland B, Burt A: Refractory obsessive compulsive disorder and ECT. Convuls Ther 10:34–42, 1994 [PubMed] Malizia AL, Cunningham VJ, Bell CJ, et al: Decreased brain GABA (A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study. Arch Gen Psychiatry 55:715–720, 1998 [PubMed] Mannuzza S, Schneier FR, Chapman TF, et al: Generalized social phobia: reliability and validity. Arch Gen Psychiatry 52:230–237, 1995 [PubMed] Mantovani A, Lisanby SH, Pieraccini F, et al: Repetitive transcranial magnetic stimulation in the treatment of obsessive compulsive disorder and Tourette's syndrome. Int J Neuropsychopharmacol 9:95–100, 2006 [PubMed] March JS, Amaya-Jackson L, Murray MC, et al: Cognitive-behavioral psychotherapy for children and adolescents with posttraumatic stress disorder after a single-incident stressor. J Am Acad Child Adolesc Psychiatry 37:585–593, 1998a March JS, Biederman J, Wolkow R, et al: Sertraline in children and adolescents with obsessive-compulsive disorder: a multicenter randomized controlled trial. JAMA 280:1752–1756, 1998b Marks I: Behaviour therapy for obsessive-compulsive disorder: a decade of progress. Can J Psychiatry 42:1021–1027, 1997 [PubMed] Marks IM, Hodgson R, Rachman S: Treatment of chronic obsessive-compulsive neurosis by in vivo exposure: a two-year follow-up and issues in treatment. Br J Psychiatry 127:349–364, 1975 [PubMed] Marks IM, Gray S, Cohen D, et al: Imipramine and brief therapist-aided exposure in agoraphobics having self-exposure homework. Arch Gen Psychiatry 40:153–162, 1983 [PubMed] Marks I, Lovell K, Noshirvani H, et al: Treatment of posttraumatic stress disorder by exposure and/or cognitive restructuring: a controlled study. Arch Gen Psychiatry 55:317–325, 1998 [PubMed] Marmar CR, Weiss DS, Schlenger WE, et al: Peritraumatic dissociation and posttraumatic stress in male Vietnam theater veterans. Am J Psychiatry 151:902–907, 1994 [Full Text] [PubMed] Maron E, Kuikka JT, Shlik J, et al: Reduced brain serotonin transporter binding in patients with panic disorder. Psychiatry Res 132:173–181, 2004 [PubMed]

Maron E, Nikopensius T, Koks S, et al: Association study of 90 candidate gene polymorphisms in panic disorder. Psychiatr Genet 15:17–24, 2005 [PubMed] Marshall JR: The treatment of night terrors associated with posttraumatic syndrome. Am J Psychiatry 132:293–295, 1975 [PubMed] Marshall RD, Beebe KL, Oldham M, et al: Efficacy and safety of paroxetine treatment for chronic PTSD: a fixed-dose, placebo-controlled study. Am J Psychiatry 158:1982–1988, 2001 [Full Text] [PubMed] Mason JW, Giller EL, Kosten TR, et al: Urinary free-cortisol levels in posttraumatic stress disorder patients. J Nerv Ment Dis 174:145–149, 1986 [PubMed] Mason JW, Giller EL, Kosten TR, et al: Elevation of urinary norepinephrine/cortisol ratio in posttraumatic stress disorder. J Nerv Ment Dis 176:498–502, 1988 [PubMed] Massion AO, Dyck IR, Shea MT, et al: Personality disorders and time to remission in generalized anxiety disorder, social phobia, and panic disorder. Arch Gen Psychiatry 59:434–440, 2002 [PubMed] Mataix-Cols D, Rauch SL, Manzo PA, et al: Use of factor-analyzed symptom dimensions to predict outcome with serotonin reuptake inhibitors and placebo in the treatment of obsessive-compulsive disorder. Am J Psychiatry 156:1409–1416, 1999 [Full Text] [PubMed] Mataix-Cols D, Wooderson S, Lawrence N, et al: Distinct neural correlates of washing, checking, and hoarding symptom dimensions in obsessive compulsive disorder. Arch Gen Psychiatry 61:564–576, 2004 [PubMed] Mataix-Cols D, Rosario Campos MC, Leckman JF: A multidimensional model of obsessive compulsive disorder. Am J Psychiatry 162:228–238, 2005 [Full Text] [PubMed] Mathew RJ, Ho BT, Kralik P, et al: Catecholamines and monoamine oxidase activity in anxiety. Acta Psychiatr Scand 63:245–252, 1981 [PubMed] Mathew SJ, Amiel JM, Coplan JD, et al: Open-label trial of riluzole in generalized anxiety disorder. Am J Psychiatry 162:2379–2381, 2005 [Full Text] [PubMed] Mattes J: More on panic disorder and mitral valve prolapse (letter). Am J Psychiatry 138:1130, 1981 Mattick RP, Peters L, Clarke JC: Exposure and cognitive restructuring for social phobia: a controlled study. Behav Ther 20:3–23, 1989 Mavissakalian M, Michelson L: Agoraphobia: relative and combined effectiveness of therapist-assisted in vivo exposure and imipramine. J Clin Psychiatry 47:117–122, 1986a Mavissakalian M, Michelson L: Two-year follow-up of exposure and imipramine treatment of agoraphobia. Am J Psychiatry 143:1106–1112, 1986b Mavissakalian M, Perel JM: Imipramine dose-response relationship in panic disorder with agoraphobia: preliminary findings. Arch Gen Psychiatry 46:127–131, 1989 [PubMed] Mavissakalian M, Perel JM: Clinical experiments in maintenance and discontinuation of imipramine therapy in panic disorder with agoraphobia. Arch Gen Psychiatry 49:318–323, 1992 [PubMed] Mavissakalian M, Perel JM: Imipramine treatment of panic disorder with agoraphobia: dose ranging and plasma levelresponse relationships. Am J Psychiatry 152:673–682, 1995 [Full Text] [PubMed] McCafferty JP, Bellew KM, Zaninelli RM: Paroxetine treatment of GAD: an analysis of response by dose. Presented at the annual meeting of the American Psychiatric Association, New Orleans, LA, May 2001 McDougle CJ, Goodman WK, Price LH, et al: Neuroleptic addition in fluvoxamine-refractory obsessive-compulsive disorder. Am J Psychiatry 147:652–654, 1990 [PubMed] McDougle CJ, Price LH, Goodman WK, et al: A controlled trial of lithium augmentation in fluvoxamine-refractory obsessive-compulsive disorder: lack of efficacy. J Clin Psychopharmacol 11:175–181, 1991a McDougle CJ, Southwick SM, Charney DS, et al: An open trial of fluoxetine in the treatment of posttraumatic stress disorder. J Clin Psychopharmacol 11:325–327, 1991b McDougle CJ, Goodman WK, Leckman JF, et al: The efficacy of fluvoxamine in obsessive-compulsive disorder: effects

of comorbid chronic tic disorder. J Clin Psychopharmacol 13:354–358, 1993a McDougle CJ, Goodman WK, Leckman JF, et al: Limited therapeutic effect of addition of buspirone in fluvoxaminerefractory obsessive-compulsive disorder. Am J Psychiatry 150:647–649, 1993b McDougle CJ, Goodman WK, Leckman JF, et al: Haloperidol addition in fluvoxamine-refractory obsessive-compulsive disorder: a double-blind, placebo-controlled study in patients with and without tics. Arch Gen Psychiatry 51:302–308, 1994 [PubMed] McDougle CJ, Epperson CN, Pelton GH, et al: A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 57:794–801, 2000 [PubMed] McFarlane AC: The aetiology of post-traumatic morbidity: predisposing, precipitating and perpetuating factors. Br J Psychiatry 154:221–228, 1989 [PubMed] McFarlane AC: Vulnerability to posttraumatic stress disorder, in Posttraumatic Stress Disorder: Etiology, Phenomenology, and Treatment. Edited by Wolf ME, Mosnaim AD. Washington, DC, American Psychiatric Press, 1990, pp 2–20 McGuire PK, Bench CJ, Frith CD, et al: Functional anatomy of obsessive-compulsive phenomena. Br J Psychiatry 164:459–468, 1994 [PubMed] McKay D: A maintenance program for obsessive-compulsive disorder using exposure with response prevention: 2-year follow-up. Behav Res Ther 35:367–369, 1997 [PubMed] McNally RJ, Metzger LJ, Lasko NB, et al: Directed forgetting of trauma cues in adult survivors of childhood sexual abuse with and without posttraumatic stress disorder. J Abnorm Psychol 107:596–601, 1998 [PubMed] Meira-Lima I, Shavitt RG, Miguita K, et al: Association analysis of the catechol-O-methyltransferase (COMT), serotonin transporter(5-HTT) and serotonin 2A receptor (5HT2A) gene polymorphisms with obsessive compulsive disorder. Genes Brain Behav 3:75–79, 2004 [PubMed] Mell LK, Davis RL, Owens D: Association between streptococcal infection and obsessive compulsive disorder, Tourette's syndrome and tic disorder. Pediatrics 116:56–60, 2005 [PubMed] Mellman TA, Knorr BR, Pigeon WR, et al: Heart rate variability during sleep and the early development of posttraumatic stress disorder. Biol Psychiatry 55:953–956, 2004 [PubMed] Mennin DS, Heimberg RG, Turk CL, et al: Preliminary evidence for an emotion dysregulation model of generalized anxiety disorder. Behav Res Ther 43:1281–1310, 2005 [PubMed] Michels R, Frances A, Shear MK: Psychodynamic models of anxiety, in Anxiety and the Anxiety Disorders. Edited by Tuma AH, Maser JD. Hillsdale, NJ, Lawrence Erlbaum, 1985, pp 595–618 Michelson D, Lydiard RB, Pollack MH, et al: Outcome assessment and clinical improvement in panic disorder: evidence from a randomized controlled trial of fluoxetine and placebo. The Fluoxetine Panic Disorder Study Group. Am J Psychiatry 155:1570–1577, 1998 [Full Text] [PubMed] Michelson D, Pollack M, Lydiard RB, et al: Continuing treatment of panic disorder after acute response: randomized, placebo-controlled trial with fluoxetine. The Fluoxetine Panic Disorder Study Group. Br J Psychiatry 174:213–218, 1999 [PubMed] Michelson L, Marchione K, Greenwald M, et al: Panic disorder: cognitive-behavioral treatment. Behav Res Ther 28:141–151, 1990 [PubMed] Miller HE, Deakin JF, Anderson IM: Effect of acute tryptophan depletion on CO2-induced anxiety in patients with panic disorder and normal volunteers. Br J Psychiatry 176:182–188, 2000 [PubMed] Millet B, Chabane N, Delorme R, et al: Association between the dopamine receptor D4 (DRD4) gene and obsessive compulsive disorder. Am J Med Genet B Neuropsychiatr Genet 116:55–59, 2003 [PubMed] Mills KI, Teesson M, Ross J, et al: Trauma, PTSD, and substance use disorders: findings from the Australian National Survey of Mental Health and Well-Being. Am J Psychiatry 163:652–658, 2006 [Full Text] [PubMed] Milrod B, Busch F, Leon AC, et al: Open trial of psychodynamic psychotherapy for panic disorder: a pilot study. Am J

et al: B lymphocyte antigen D8/17: a peripheral marker for childhood-onset obsessive-compulsive disorder and Tourette's syndrome? Am J Psychiatry 154:402–407.Psychiatry 157:1878–1880. Busch F. et al: Reduced serotonin type 1A receptor binding in panic disorder. Nickel C. double blind. Eur Neuropsychopharmacol 3:143–152. Polinsky RJ. 2001 [PubMed] Mindus. et al: A 24 week randomized. 2000 [Full Text] [PubMed] Milrod B. placebo controlled study of escitalopram for the prevention of generalized social anxiety disorder. Psychol Med 30:797–804. Noyes R. et al: Social phobia in a population-based female adolescent twin sample: co-morbidity and associated suicide-related symptoms. 1981 [PubMed] Nemiah JC: The psychodynamic view of anxiety: an historical approach. 1999 [PubMed] Murphy TK. et al: A double-blind. J Neurosci 24:589–591. Yamada K. Nugent AC. 1993 [PubMed] Montgomery SA. et al: Citalopram 20 mg. Behav Res Ther 37:863–868. 2001 [PubMed] Montgomery SA. Mathews A. doubleblind. Lan T. 2000a Nestadt G. pp 277–303 Nestadt G. in Handbook of Anxiety. Biol Psychiatry 57:901–910. Leon AC. 2000b Neumeister A. 2005 [PubMed] Mundo E. Amsterdam. Psychiatr Clin North Am 15:921–938. Burrows GD. Durr-Pal N. 2000 [PubMed] Montgomery SA. Nickel MK. Int J Clin Psychopharmacol 16:75–86. 2005 [PubMed] Mowrer O: A stimulus response analysis of anxiety and its role as a reinforcing agent. Elsevier. et al: Complex segregation analysis provides compelling evidence for a major gene underlying obsessive-compulsive disorder and for heterogeneity by sex. Psychol Bull 131:785–795. 2005 [PubMed] Nee LE. Am J Psychoanal 41:115–120. et al: Evidence that variation in the peripheral benzodiazepine receptor (PBR) gene influences susceptibility to panic disorder. The Netherlands. Samuels J. 1988. Arch Gen Psychiatry 57:358–363. Vol 1. 2005 [PubMed] Mogg K. Nil R. Bradley BP: Biases in eye movements to threatening facial expressions in generalized anxiety disorder and depressive disorder. Behav Res Ther 27:317–323. Edited by Roth M. Sam F. Jenike MA: Neurosurgical treatment of malignant obsessive-compulsive disorder. et al: Mirtazapine treatment of social phobia in women: a randomized. Goodman WK. 1982 Nelson EC. Stein DJ. Richter MA. The Lilly European OCD Study Group. Caine ED. McIntyre A. 2004 [PubMed] . 40 mg. Weinman J: Selective processing of threat cues in anxiety states: a replication. Millar N. Bain E. et al: A pilot open trial of brief psychodynamic psychotherapy for panic disorder. 1989 [PubMed] Mogg K. et al: A family study of obsessive-compulsive disorder. 2006 [PubMed] Nakao T. Bucholz KK. 60mg are all effective and well tolerated compared with placebo in obsessive compulsive disorder. Am J Hum Genet 67:1611–1616. Grant JD. Nakagawa A. 2000 [PubMed] Nemiah JC: A psychoanalytic view of phobias. Iwayama Y. 1997 [Full Text] [PubMed] Nakamura K. placebo-controlled study. J Clin Psychopharmacol 25:580–583. Am J Med Genet 141:222–226. et al: Brain activation of patients with obsessive compulsive disorder during neuropsychological and symptom provocation tasks before and after symptom improvement: a functional magnetic resonance imaging study. J Clin Psychiatry 66:1270–1278. et al: Gilles de la Tourette syndrome: clinical and family study of 50 cases. 1992 [PubMed] Mitte K: Meta-analysis of cognitive-behavioral treatments for generalized anxiety disorder: a comparison with pharmacotherapy. Osterheider M. Riddle M. 2000 [Full Text] [PubMed] Muris P. 1939 Muehlbacher M. placebo-controlled study of fluoxetine in patients with DSM-III-R obsessive-compulsive disorder. J Psychother Pract Res 10:239–245. Schmidt H. Ann Neurol 7:41–49. Samuels J. Kasper S. Yoshiura T. Fudge MW. et al: Is the 5-HT(1Dbeta) receptor gene implicated in the pathogenesis of obsessivecompulsive disorder? Am J Psychiatry 157:1160–1161. Psychol Rev 46:553–565. J Abnorm Psychol 109:695–704. Meckelbach H: The structure of specific phobia symptoms among children and adolescents.

J Am Acad Child Adolesc Psychiatry 39:1313–1315. 2000 [PubMed] Ost LG. 1999 [PubMed] . 1993 [PubMed] Nutt DJ: Altered central 2-adrenoreceptor sensitivity in panic disorder. Glue P. J Clin Psychopharmacol 24:106–108. et al: Valproate monotherapy in the treatment of civilian patients with non combat related posttraumatic stress disorder: an open label study. Koran LM. Gould RA. Lenane M. Gabriels LA. J Clin Psychopharmacol 21:335–339. 1992 [PubMed] Nicolson R. Best SR. Lawson C. Metzger LJ. Sachs GS. J Clin Psychiatry 67:15–22. Compr Psychiatry 32:283–294. et al: An open trial of plasma exchange in childhood-onset obsessive-compulsive disorder without poststreptococcal exacerbations. cognitive behavior therapy in the treatment of panic disorder. Br J Psychiatry 168:462–469. et al: Double-blind. Yassouridis A. doubleblind. et al: Long term electrical capsular stimulation in patients with obsessive compulsive disorder.Neylan TC. Quercioli L. 1995 [PubMed] Ost LG. 1989 [PubMed] Nutt DJ. et al: Environmental factors related to the outcome of panic disorder: a seven-year follow-up study. Thulin U. 1995 [PubMed] Orr SP. 2004 [PubMed] Otte C. Breitholtz E: Applied relaxation versus cognitive therapy in the treatment of generalized anxiety disorder. et al: Flumazenil provocation of panic attacks: evidence for altered benzodiazepine receptor sensitivity in panic disorder. Yaryura-Tobias JA: Onset of obsessive-compulsive disorder in pregnancy. Am J Psychiatry 149:947–950. Westling BE: Applied relaxation vs. Paiva RS. 1993 [Full Text] [PubMed] Otto MW. et al: The Galway study of panic disorder. III: outcome at 5 to 6 years. J Anxiety Disord 14:345–358. J Abnorm Psychol 109:290–298. Brophy J. et al: A comparison of the efficacy of clonazepam and cognitive-behavioral group therapy for the treatment of social phobia. 1991 [PubMed] Noyes R Jr. 1996 [PubMed] Oehrberg S. 2000 [PubMed] Ost LG. 2001 [PubMed] Neziroglu F. Clancy J. Neurosurgery 52:1263–1272. Psychol Bull 129:52–72. 2000 [PubMed] Ninan PT. et al: Fluvoxamine and sleep disturbances in posttraumatic stress disorder. et al: Predictors of posttraumatic stress disorder and symptoms in adults: a meta analysis. Reich JH. 1990 [PubMed] Nuttin BJ. 2000 [PubMed] Ozer EJ. et al: High-dose sertraline strategy for nonresponders to acute treatment for obsessivecompulsive disorder: a multicenter double-blind trial. 2003 [PubMed] O'Rourke D. et al: Discontinuation of benzodiazepine treatment: efficacy of cognitive-behavioral therapy for patients with panic disorder. Reich JH. 2006 [PubMed] Noyes R Jr. Schoenfeld FB. placebo-controlled study. Anemone R. Kiev A. Christiansen PE. Swedo SE. et al: Outcome of panic disorder: relationship to diagnostic subtypes and comorbidity. 1990 [PubMed] Noyes R Jr. et al: Personality traits associated with panic disorder: change associated with treatment. J Trauma Stress 14:461–467. et al: De novo conditioning in trauma-exposed individuals with and without posttraumatic stress disorder. 2004 [PubMed] Otto MW. Pollack MH. Behnke K. Woodman C. crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. Cosyns PR. Suelzer M. J Nerv Ment Dis 181:529–538. Metzler TJ. Arch Gen Psychiatry 47:917–925. Arch Gen Psychiatry 47:809–818. Eur Psychiatry 14:101–106. 2003 [PubMed] Palatnik A. Br J Psychiatry 167:374–379. Fux M. Christiansen J. Behav Res Ther 33:145–158. Wiedemann K. Pollack MH. Am J Psychiatry 150:1485–1490. Arch Gen Psychiatry 46:165–169. Ramnero J: Cognitive behavior therapy vs. Behav Res Ther 42:1105–1127. 2001 [PubMed] Pallanti S. et al: Paroxetine in the treatment of panic disorder: a randomised. exposure in vivo in the treatment of panic disorder with agoraphobia. Lipsey TL. Lasko NB. Frolov K. et al: Citalopram for treatment-resistant obsessive-compulsive disorder. Fahy TJ. Behav Res Ther 38:777–790.

Lancet 354:1153–1158. J Clin Psychiatry 60:379–384. 2000 [PubMed] Pande AC.Pallanti S. et al: [18F] FDG PET study in obsessive-compulsive disorder: a clinical/metabolic correlation study after treatment. and their combination for children and adolescents with obsessive compulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial. Arch Gen Psychiatry 45:429–436. et al: Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo controlled. Zohar-Kadouch R. 1991 [PubMed] Pauls DL. Quercioli L. multicenter study. Leitman SF. Cortese BM. 2000 [PubMed] Phan KL. Int Clin Psychopharmacol 15:297–301. et al: Longitudinal course of posttraumatic stress disorder and posttraumatic stress disorder symptoms in a community sample of adolescents and young adults. 1999 [PubMed] Perry BD. 2003 [PubMed] Pato MT. Colombo C. Bussi R. Garvey MA. Jefferson JW. Neuroreport 16:183–186. Fitzgerald DA. J Clin Psychopharmacol 20:467–471. 1995 [PubMed] Peri T. Dell'Osso L. J Clin Psychopharmacol 24:141–149. J Clin Psychiatry 65:1394–1399. J Clin Psychopharmacol 19:341–348. Edited by Anrep GV. Stein MB. Mensour B. 2004 Perani D. 2004 [PubMed] Pande AC. et al: Anterior cingulated neurochemistry in social anxiety disorder: 1H-MRS at 4 Tesla. et al: Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. Hill JL. Taylor SF. 2006b . Jefferson JW. et al: Corticolimbic blood flow during nontraumatic emotional processing in posttraumatic stress disorder. JAMA 292:1969–1976. Am J Psychiatry 162:1320–1327. Am J Psychiatry 148:127–129. et al: Controlled comparison of buspirone and clomipramine in obsessive-compulsive disorder. Pollack MH. sertraline. Arch Gen Psychiatry 43:1180–1182. 1999 [PubMed] Perna G. Levesque J. et al: Treatment of social phobia with gabapentin: a placebo-controlled study. et al: Placebo-controlled study of gabapentin treatment of panic disorder. Nathan PJ. Am J Psychiatry 144:1511–1512. Orr SP. Britton JC. 1988 [PubMed] Pediatric OCD Treatment Study Team: Cognitive behavior therapy. Bruscholi M: Response acceleration with mirtazapine augmentation of citalopram in obsessive compulsive disorder patients without comorbid depression: a pilot study. III: discontinuation effects. 2006a Phan KL. Neuroimage 18:401–409. Kuch K. 2000 [PubMed] Perkonigg A. Davidson JRT. Fitzgerald DA. et al: Gilles de la Tourette's and obsessive-compulsive disorder: evidence supporting a genetic relationship. Pigott TA. et al: Risperidone augmentation in refractory obsessive-compulsive disorder: an open-label study. Giller EL Jr. 1987 [PubMed] Pfanner C. 1986 [PubMed] Pavlov IP: Conditional Reflexes: An Investigation of the Physiological Activity of the Cerebral Cortex (1927). Marazziti D. et al: Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. 1988 [PubMed] Pato MT. et al: "Change the mind and you change the brain": effects of cognitive behavioral therapy on the neural correlates of spider phobia. Biol Psychiatry 59:424–429. Zohar J. Ben Shakhar G. 2005 [PubMed] Phan KL. Feltner DE. 1999 [PubMed] Pande AC. et al: Association between amygdala hyperactivity to harsh faces and severity of social anxiety in generalized social phobia. Crockatt J. Southwick SM: Altered plasma alpha2-adrenergic binding sites in posttraumatic stress disorder (letter). Swinson RP. Biol Psychiatry 47:512–519. Leckman JF. Pfister H. New York. Bressi S. Bover. Towbin KE. 2004 [PubMed] Paquette V. 1960 Pecknold JC. et al: Return of symptoms after discontinuation of clomipramine in patients with obsessive-compulsive disorder. et al: Psychophysiological assessment of aversive conditioning in posttraumatic stress disorder. Allevi L et al: Sensitivity to 35% carbon dioxide in patients with generalized anxiety disorder. Br J Psychiatry 166:244–250. Arch Gen Psychiatry 63:184–192. Am J Psychiatry 145:1521–1525. 2005 [Full Text] [PubMed] Perlmutter SJ.

et al: Avoidant personality disorder and social phobia: distinct enough to be separate disorders? Acta Psychiatr Scand 112:208–214. Pini S. 1998 [Full Text] [PubMed] Pohl RB. NeuroRx 3:69–81. J Clin Psychiatry 62:350–357. et al: Laboratory procedure for the inducement of flashbacks. et al: Response to 5% carbon dioxide in children and adolescents: relationship to panic disorder in parents and anxiety disorders in subjects. Arch Gen Psychiatry 47:541–544. L'Heureux F. and placebo. placebo controlled study of trazodone in patients with obsessive-compulsive disorder. et al: Paroxetine in the treatment of generalized anxiety disorder: results of a placebo-controlled. 2001 [PubMed] . J Clin Psychopharmacol 12:11–18. New York. 2006 [PubMed] Pujol J. Biol Psychiatry 51:189–192. J Clin Psychopharmacol 21:104–107. Roy-Byrne PP. Grilo CM. 1982. 2002 [PubMed] Pittenger C. Robertson Nay R. Br J Psychiatry 166:424–443. Hodgson RJ: Obsessions and Compulsions. Clary CM. McClure JN: Lactate metabolism in anxiety neurosis. Neuroreport 17:361–363. Feltner DE. N Engl J Med 277:1329–1336. Sanislow CA. van der Kolk BA. et al: A double-blind study of adjuvant buspirone hydrochloride in clomipramine-treated patients with obsessive-compulsive disorder. 2005 [PubMed] Pollack MH. 1992a Pigott TA. L'Heureux F. Sanders KM. 2001 [PubMed] Pollack MH. for the treatment of generalized anxiety disorder. Fieve RR. Edited by Soloman J.Piccinelli M. Pan H. Prentice-Hall. et al: A double-blind. 1999 [PubMed] Rainey JM Jr. et al: Increased brainstem volume in panic disorder: a voxel-based morphometric study. Alonso P. diazepam. et al: Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Zaninelli R. Hill JL. Orr SP. Pollack MH. NJ. Goddard A. et al: The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebo-controlled study. J Anxiety Disord 4:267–292. et al: Mapping structural brain alterations in obsessive compulsive disorder. J Clin Psychopharmacol 12:156–162. et al: Efficacy of pregabalin in the treatment of generalized anxiety disorder: doubleblind. Pato MT. Coric V: Glutamate-modulating drugs as novel pharmacotherapeutic agents in the treatment of obsessive compulsive disorder. pp 129–140 Rachman SJ. et al: A controlled comparison of cognitive-behaviour therapy. 2005 [PubMed] Pitman RK. 2005 [PubMed] Rapaport MH. 1990 [PubMed] Pitman RK. Arch Gen Psychiatry 44:970–975. 1991 [PubMed] Pigott TA. Bellantuono C. J Clin Psychopharmacol 25:151–158. Rubenstein CS. Aleem A. Swanson V. Tuescher O. 2005 [PubMed] Power KG. Van Ameringen M. Plenum. et al: Psychophysiological assessment of post-traumatic stress disorder imagery in Vietnam combat veterans. Orr SP. Forgue DF. J Clin Psychiatry 66:1401–1408. Wolkow RM. Klein RG. et al: Efficacy of drug treatment in obsessive-compulsive disorder: a meta-analytic review. et al: A controlled comparison of adjuvant lithium carbonate or thyroid hormone in clomipramine-treated patients with obsessive-compulsive disorder. 1987 [PubMed] Pitman RK. Zusman RM. Clary CM: Sertraline in the treatment of panic disorder: a double-blind multicenter trial. J Clin Psychopharmacol 11:242–248. alone and in combination. Rachman S: Memory bias in obsessive-compulsive disorder. et al: Panic disorder and response to sertraline: the effect of previous treatment with benzodiazepines. Am J Psychiatry 155:1189–1195. Arch Gen Psychiatry 61:720–730. Babkin J: Hidden psychiatric diagnosis in the alcoholic. in Alcoholism and Clinical Psychiatry. Krystal JH. et al: Naloxone-reversible analgesic response to combat-related stimuli in posttraumatic stress disorder: a pilot study. Am J Psychiatry 144:1317–1319. Soriano Mas C. 2004 [PubMed] Quitkin F. 1967 [PubMed] Pohl RB. 1987 [PubMed] Ralevski E. 2006 [PubMed] Pitts FN. Ortiz A. 1992b Pine DS. flexible-dosage trial. Simpson RJ. 1980 Radomsky AS. Behav Res Ther 37:605–618. Englewood Cliffs. 1995 [PubMed] Pigott TA. Arch Gen Psychiatry 62:73–80. placebo-controlled comparison of BID versus TID dosing. 1990 Protopopescu X. L'Heureux F.

Am J Psychiatry 143:317–322. et al: One-month prevalence of mental disorders in the United States. 1979. Wright I. van der Kolk BA. Arch Gen Psychiatry 53:380–387. Neuropsychopharmacology 27:782–791. Schweizer E. Savage CR. based on five Epidemiologic Catchment Area sites. 1986 [PubMed] Rasmussen S. Am J Psychiatry 160:749–756. et al: Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. et al: Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study. Martis B. Haier RJ. Downing R. DeMartinis N. and shyness: putting the personality back into personality disorders. et al: A symptom provocation study of posttraumatic stress disorder using positron emission tomography and script-driven imagery. Am J Psychiatry 160:371–373. Arch Gen Psychiatry 61:1136–1144. et al: A 2-year study of sertraline in the treatment of obsessive-compulsive disorder. et al: Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo controlled study.Raskind MA. Jenike MA. Tannenbaum L. et al: A comparison of cognitive processing therapy with prolonged exposure and a waiting condition for the treatment of chronic posttraumatic stress disorder in female rape victims. 1995 [PubMed] Rauch SL. Garcia-Espana F. 2002 [PubMed] Ressler KJ. Biol Psychiatry 50:659–667. 1996 [PubMed] Rauch SL. Am J Psychiatry 157:1973–1979. Arch Gen Psychiatry 45:977–986. J Neurosurg 104:558–565. et al: Regional cerebral blood flow measured during symptom provocation in obsessive-compulsive disorder using oxygen 15-labeled carbon dioxide and positron emission tomography. and diazepam. 2003 [Full Text] [PubMed] Rasmussen SA. pp 153–203 Regier DA. et al: Cerebral metabolic correlates as potential predictors of response to anterior cingulotomy for obsessive compulsive disorder. Arch Gen Psychiatry 50:884–895. Arch Gen Psychiatry 52:20–28. 2004 [PubMed] Rettew DC: Avoidant personality disorder. in Phenomenology and Treatment of Anxiety. Jenike MA. 2006 [PubMed] Redmond DE Jr: New and old evidence for the involvement of a brain norepinephrine system in anxiety. Burke JD Jr. Edited by Fann WE. 1989 [PubMed] Resick PA. Zaninelli R. 1997 [PubMed] Rauch SL. Fisler RE. Alpert NM. Boyd JH. 2003 [Full Text] [PubMed] . et al: A functional neuroimaging investigation of deep brain stimulation in patients with obsessive compulsive disorder. Nishith P. Csanalosi I. McCafferty J: Paroxetine treatment of generalized anxiety disorder: a double-blind. trazodone. Dougherty DD. 1993 [PubMed] Rickels K. 2004 [PubMed] Rauch SL. Malone D. Arch Gen Psychiatry 45:444–450. 2002 [PubMed] Rauch SL. Alpert NM. 2000 [Full Text] [PubMed] Rickels K. 1988 [PubMed] Reist C. New York. J Consult Clin Psychol 70:867–879. et al: A controlled trial of desipramine in 18 men with posttraumatic stress disorder. 2001 [PubMed] Rauch SL. DuBoff E. generalized social phobia. Whalen PJ. et al: Imipramine and buspirone in treatment of patients with generalized anxiety disorder who are discontinuing long-term benzodiazepine therapy. Peskind ER. placebocontrolled study. et al: Antidepressants for the treatment of generalized anxiety disorder: a placebocontrolled comparison of imipramine. Kauffmann CD. et al: Long-term treatment of anxiety and risk of withdrawal: prospective comparison of clorazepate and buspirone. Am J Psychiatry 146:513–516. et al: A positron emission tomographic study of simple phobic symptom provocation. Arch Gen Psychiatry 51:62–70. 2000 [PubMed] Rauch SL. Tsuang MT: Clinical characteristics and family history in DSM-III obsessive compulsive disorder. Biol Psychiatry 47:769–776. 1988 [PubMed] Rickels K. Karacan I. Cosgrove GR. et al. Rothbaum BO. Weaver TL. Int Clin Psychopharmacol 12:309–316. Spectrum. Harv Rev Psychiatry 8:283–297. Hackett E. Alpert NM. Pokorny AD. et al: Predictors of fluvoxamine response in contamination-related obsessive compulsive disorder: a PET symptom provocation study. 1994 [PubMed] Rauch SL. Dougherty DD. Shin LM. Biol Psychiatry 55:946–952. Kanter ED. Schweizer E. et al: A magnetic resonance imaging study of cortical thickness in animal phobia. 2000 [PubMed] Rickels K.

Becker ES: A comparison of attentional biases and memory biases in women with social phobia and major depression. Khan A: A double blind placebo controlled study of a flexible dose of venlafaxine ER in adult outpatients with generalized social anxiety disorder. Loo CK. et al: Clinical aspects of chronic use of alprazolam and lorazepam. J Clin Psychiatry 62:617–622.E. open label study. et al: Should excessive worry be required for a diagnoses of generalized anxiety disorder? Results from the U. Moroz G. Greenblatt DJ. Hamner MB. Craske MG. Lane M. Neuroreport 16:927–931. Somer G. National Comorbidity Survey replication. 2001 [PubMed] Sakai Y. et al: Pregabalin for treatment of generalized anxiety disorder: a 4-week. Gilbert A. et al: Reduced benzodiazepine sensitivity in panic disorder. Goodman W. Arch Gen Psychiatry 54:824–830. et al: A randomized effectiveness trial of cognitive-behavioral therapy and medication for primary care panic disorder. 1997 [PubMed] Rosenberg DR. Wroe AL. et al: Symptom dimensions in obsessive compulsive disorder: prediction of cognitive behavior therapy outcome. 2001 [PubMed] Rothbaum Bo. Kose S. 1998 [PubMed] Rosenberg DR. Moritz S. et al: Quetiapine improves sleep disturbances in combat veterans with PTSD: sleep data from a prospective. Beoni AM. Swinson RP: Interpretations for anxiety symptoms in social phobia. J Clin Psychopharmacol 24:488–496. Behav Res Ther 39:129–138. Yaryura-Tobias JA. and discontinuance. 2005 [PubMed] Sachdev PS. Keshavan MS: A. safety. J Am Acad Child Adolesc Psychiatry 40:222–229. et al: Frontostriatal measurement in treatment-naïve children with obsessive-compulsive disorder. Ready D. Feltner DE. Bennett Research Award: toward a neurodevelopmental model of obsessivecompulsive disorder. et al: Long-term treatment of obsessive-compulsive disorder after an acute response: a comparison of fluoxetine versus placebo. Biol Psychiatry 43:767–773. et al: Right versus left prefrontal transcranial magnetic stimulation for obsessive compulsive disorder: a preliminary investigation. Gledhill A. Bowden CL: Clonazepam in the treatment of panic disorder with or without agoraphobia: a dose–response study of efficacy. Reeve EA. Biol Psychiatry 48:294–300. Clark DM: Respiratory control in the treatment of panic attacks: replication and extension with concurrent measurement of behaviour and pCO2. et al: Responsibility attitudes and interpretations are characteristic of obsessive . Pollack MH. Ricke S. Keshavan MS. 2001 [PubMed] Rinck M.S. Benazon NR. Arch Gen Psychiatry 62:1022–1033. 2004 [PubMed] Rickels K. et al: Peripheral benzodiazepine receptor messenger RNA is decreased in lymphocytes of generalized anxiety disorder patients. 1997 [PubMed] Rosenberg DR. Clonazepam Panic Disorder Dose-Response Study Group. J Clin Psychiatry 62:981–984. J Clin Psychopharmacol 25:387–388. Hodges LF. multicenter. Br J Psychiatry 148:526–532. J Clin Psychopharmacol 17:390–400. 2005 [PubMed] Robert S.Rickels K. Tamura R. Mangano R. Arch Gen Psychiatry 47:534–538. 2001 [PubMed] Rosenbaum JF. Jones DRO. J Clin Psychopharmacol 21:46–52. double-blind. 2005 [PubMed] Rocca P. et al: Cerebral glucose metabolism associated with a fear network in panic disorder. Arch Gen Psychiatry 62:290–298. 1995 [Full Text] [PubMed] Romano S. 2006 [PubMed] Ruscio AM. 2005 [PubMed] Salkovskis PM. O'Hearn KM. Nishikawa M. Biol Psychiatry 43:623–640. et al: Fluvoxamine for children and adolescents with obsessive-compulsive disorder: a randomized. Cowley DS. controlled. 1986 [PubMed] Salkovskis PM. Busto U. Kumano H. 2005 [PubMed] Riddle MA. placebo-controlled trial of pregabalin and alprazolam. 1990 [PubMed] Roy-Byrne PP. Antony MM. 2000 [PubMed] Roth D. 2001 [PubMed] Roy-Byrne PP. multicenter trial. et al: Virtual reality exposure therapy for Vietnam veterans with posttraumatic stress disorder. McBrider R. Eva C. et al: Thalamic volume in pediatric obsessive-compulsive disorder patients before and after cognitive behavioral therapy. Stein MB. 2005 [PubMed] Rufer M. Acta Psychiatr Scand 113: 440–446. Am J Psychiatry 152:1161–1167. Psychol Med 35:1761–1772. J Abnorm Psychol 114:62–74. 1998 [PubMed] Romach M. Roy-Byrne P.

et al: The OCD Collaborative Genetics Study: methods and sample description. Liebowitz MR. Plenum. Zubragel D. Behav Res Ther 38:347–372. Snidman N. Greenberg BD. Peri T. Stoessel PW. open-label trial. fixed-dose. et al: Stress doses of hydrocortisone. Int Clin Psychopharmacol 14:353–356. 2003 [PubMed] Sepede G. 2006 [PubMed] Sanderson WC. 1999 [PubMed] Schneier F. 1999 [PubMed] Schwartz JM. placebo controlled assessment of combined clonazepam with paroxetine compared with paroxetine monotherapy for generalized social anxiety disorder. New York.5% carbon dioxide-enriched air. Ho ML. Barlow DH: The influence of an illusion of control on panic attacks induced via inhalation of 5. 2002 [PubMed] Schelling G. Wang D. Am J Psychiatry . et al: Low dopamine D2 binding potential in social phobia. et al: Incidence and prediction of posttraumatic stress disorder symptoms in severely injured accident victims. 2003 [PubMed] Saxe G. et al: Subcortical correlates of differential classical conditioning of aversive emotional reactions in social phobia. Armore M. Klaghofer R. Rapee RM. et al: Antidepressant discontinuation in the context of cognitive behavioral treatment for panic disorder. Kessler C. 1989 [PubMed] Sarchiapone M. Brody AL. Stein DJ: Inositol augmentation of serotonin reuptake inhibitors in treatment-refractory obsessivecompulsive disorder: an open trial. Salerno RM. Turner SM. Roozendaal B. Stein MB: Double blind. Papadimitriou GN. Edited by Mavissakalian M. Biol Psychiatry 45:863–871. Am J Psychiatry 157:457–459. traumatic memories. 2001 [PubMed] Saxena S. Abi-Dargham A. Linden M. J Clin Psychiatry 65:244–248. et al: Predictors of PTSD in injured trauma survivors: a prospective study. J Am Acad Child Adolesc Psychiatry 38:1008–1015. Michelson L. Biol Psychiatry 55:627–633. 1989 Shalev AY. et al: Differential cerebral metabolic changes with paroxetine treatment of obsessive compulsive disorder vs major depression. 2004 [PubMed] Senkowski D. Int Clin Psychopharmacol 18:35–38. Praeger. Westenberg HG: Efficacy of quetiapine in generalized social anxiety disorder: results from an open label study. in Obsessive-Compulsive Disorder: Psychological and Pharmacological Treatment. 2000 [PubMed] Salzman L: Comments on the psychological treatment of obsessive-compulsive patients. 1999 [PubMed] Seedat S. et al: Systematic changes in cerebral glucose metabolic rate after successful behavior modification treatment in obsessive-compulsive disorder. Arch Gen Psychiatry 53:109–113. Arch Gen Psychiatry 46:157–162. Baxter LR. J Clin Psychopharmacol 26:45–49. et al: Risperidone augmentation of SRI treatment for refractory obsessive-compulsive disorder. 2004 [PubMed] Schmidt NB. Stoddard F. 1996 [PubMed] Saxena S. 1985. Riddle MA. 2006 [PubMed] Sevy S. Kagan J: Adolescent social anxiety as an outcome of inhibited temperament in childhood. J Am Acad Child Adolesc Psychiatry 40:915–921. Am J Med Genet B Neuropsychiatr Genet 141:201–207. Surmont DW. pp 155–165 Samuels JF. De Risio S. J Clin Psychiatry 57:303–306. 2005 [PubMed] Schwartz C. Arch Gen Psychiatry 59:250–261. 2000 [Full Text] [PubMed] Schnyder U. Biol Psychiatry 53:304–314. New York. Behav Res Ther 40:67–73. and Legal Issues. Biol Psychiatry 15:141–152. J Clin Psychiatry 66:540–542. Treatment. Trakowski JH. Weiss U. 2001 Schutters SI. Am J Psychiatry 158:595–599. et al: Mirtazapine in the treatment of panic disorder: an open-label trial.compulsive disorder. Canetti L. 2002 [PubMed] Schneider F. 1984 Seedat S. Ferro FM: Olanzapine augmentation in treatment-resistant panic disorder: a 12-week. 1996 [PubMed] Scrignar CB: Post-Traumatic Stress Disorder: Diagnosis. Moergeli H. et al: Noradrenergic function in generalized anxiety disorder. Kilger E. Mancini E. Courtney D. and healthy subjects. Wollaway-Bickel K. major depressive disorder. and symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized study. et al: Evidence for disturbed cortical signal processing and altered serotonergic neurotransmission in generalized anxiety disorder. Van Megen HJ. et al: Relationship between acute morphine and the course of PTSD in children with burns. Bystritsky A.

Freedman S. Am J Psychiatry 157:1229–1235. Freedman S. J Clin Psychopharmacol 25:497–499. 2005 [PubMed] Southwick SM. et al: Stress and vulnerability to posttraumatic stress disorder in children and adolescents. Orr SP. Torgensen S. Cooper AM. Rynn MA. Huppert JD. Munoz DM. J Trauma Stress 5:97–101. Brechman-Toussant M: Social skills. Zlotnick C. Gorfinkle KS. 1999 [PubMed] Simpson HB. 2000 [Full Text] [PubMed] Simon NM. Emmanuel N. Burnham DB. 2005 [PubMed] Silva RR. Alpert M. Mandoki M. Biol Psychiatry 26:349–355. 2005 [PubMed] Shin LM. history of trauma. Wright CA. Am J Psychiatry 155:630–637. et al: Personality disorders. Foa EB. Arch Gen Psychiatry 55:553–559. Arch Gen Psychiatry 61:168–176. 1993 [PubMed] Smith MA. Liebowitz MR. Acta Psychiatr Scand 88:85–92. 2004 [PubMed] Shay J: Fluoxetine reduces explosiveness and elevates mood of Vietnam combat vets with PTSD. et al: Noradrenergic and serotonergic function in posttraumatic stress disorder. Petkova E. Iyengar MK. 1999 [PubMed] Skre I. et al: Visual imagery and perception in posttraumatic stress disorder: a positron emission tomographic investigation. Liebowitz MR: Cognitive-behavioral therapy as an adjunct to serotonin reuptake inhibitors in obsessive-compulsive disorder: an open trial. Donovan C. and cognitive features of childhood social . Klerman GL. Ward HE. Rickels K: Open-label pilot study of ziprasidone for refractory generalized anxiety disorder. Biol Psychiatry 55:553–555. et al: The corticotropin releasing hormone test in patients with posttraumatic stress disorder. Kosslyn SM. et al: A psychodynamic model of panic disorder. 1989 [PubMed] Smoller JW. Davidson J. 1998a Shalev AY. Onstad S. 2005 Skoog G. 1996 Shalev AY. Peri T. et al: A double blind. Depress Anxiety 19:225–233. J Clin Psychiatry 60:584–590. Arch Gen Psychiatry 56:121–127. Compr Psychiatry 41:312–325. Sahar T. 1997 [PubMed] Spence SH. 1998b Shapira NA. 1993 [Full Text] [PubMed] Sheehan DV. Arch Gen Psychiatry 62:273–281. Carson MA. Yamaki LH. Fagerness JA. Psychopharmacol Bull 37:66–72. J Clin Psychiatry 66:34–40. et al: A prospective study of heart rate response following trauma and the subsequent development of posttraumatic stress disorder. et al: A twin study of DSM-III-R anxiety disorders. Arch Gen Psychiatry 54:749–758. 2004 [PubMed] Shin LM.153:2219–2225. 1992 Shea MT. et al: Post treatment effects of exposure therapy and clomipramine in obsessive compulsive disorder. Am J Psychiatry 150:859–866. et al: Bupropion sustained release for panic disorder. et al: Efficacy and tolerability of controlled-release paroxetine in the treatment of panic disorder. et al: A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Bremner JD. McNally RJ. Ballenger J. Skoog I: A 40-year follow-up of patients with obsessive-compulsive disorder. 2003 [PubMed] Simpson HB. and posttraumatic stress disorder in subjects with anxiety disorders. 2005 [PubMed] Snyderman SH. Ritchie JC. Dolan R. social outcomes. J Clin Psychiatry 67:269–276. et al: The corticotropin-releasing hormone gene and behavioral inhibition in children at risk for panic disorder. 1997 [PubMed] Shin LM. 2004 [PubMed] Simpson HB. Krystal JH. et al: Response versus remission in obsessive compulsive disorder. Biol Psychiatry 57:1485–1492. placebo controlled trial of olanzapine addition in fluoxetine refractory obsessive compulsive disorder. et al: Prospective study of posttraumatic stress disorder and depression following trauma. 2000 Shear MK. Cannstraro PA. Arch Gen Psychiatry 54:233–241. et al: Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD.

Cochrane Database Syst Rev (1):CD002795. Hazen AL. Larsen DK. Sareen J. 1990 [PubMed] Stein DJ. Walker JR. Gergel I. 1997 [Full Text] [PubMed] Stein MB. Kozak MV. Hollander E: Meta-analysis of pharmacotherapy trials for obsessive-compulsive disorder. J Clin Psychiatry 64:1322–1327. crossover study. J Clin Psychiatry 63:152–155. double-blind. Feutsch M. Asmundson GJ: Effects of three PTSD treatments on anger and guilt: exposure therapy. et al: Peripheral catecholamine levels and the symptoms of anxiety: studies in patients with and without pheochromocytoma. Biol Psychiatry 45:840–845. Versiani M. Nesse RM. Brechman TM: The treatment of childhood social phobia: the effectiveness of a social skills training-based.phobia. 1999 [PubMed] Stahl SM. 1999 [PubMed] Spence SH. Biol Psychiatry 36:548–558. Walker JR. et al: Increased amygdala activation to angry and contemptuous faces in generalized . 1994 [Full Text] [PubMed] Spivak B. Kean YM: Disability and quality of life in social phobia: epidemiologic findings. Biol Psychiatry 37:224–228. 2006 Stein MB. J Abnorm Psychol 108:211–221. et al: Low platelet-poor plasma concentrations of serotonin in patients with combat-related posttraumatic stress disorder. Am J Psychiatry 158:1725–1727. et al: Fluvoxamine treatment of social phobia (social anxiety disorder): a doubleblind. eye movement desensitization and reprocessing. Hair. Am J Psychiatry 152:1168–1173. 1995a Stein MB. and relaxation training. 2006 [PubMed] Starkman MN. Li D: Escitalopram in the treatment of panic disorder: a randomized. et al: Social anxiety disorder and the risk of depression: a prospective community study of adolescents and young adults. Ipser JC. Int Clin Psychopharmacol 10:11–18. 2000 [Full Text] [PubMed] Stein MB. placebocontrolled trial. et al: Childhood physical and sexual abuse in patients with anxiety disorders and in a community sample. et al: Does cognitive behavior therapy assist slow-taper alprazolam discontinuation in panic disorder? Am J Psychiatry 151:876–881. Donovan C. placebo controlled. 1999 [Full Text] [PubMed] Stein MB. et al: Pindolol potentiation of paroxetine for generalized social phobia: a double blind. et al: Paroxetine treatment of generalized social phobia (social anxiety disorder): a randomized controlled trial. et al: Genetic linkage to the serotonin transporter protein and 5HT2A receptor genes excluded in generalized social phobia. Sareen J. cognitive-behavioural intervention. Millar TW. Cameron OG. Taylor S. Gregg SF. J Trauma Stress 19:19–28. et al: Predictors of response to pharmacotherapy in social anxiety disorder: an analysis of 3 placebo controlled paroxetine trials. Vered Y. 1998b Stein MB. Spadaccine E. JAMA 280:708–713. T. et al: 3H paroxetine binding to platelets of patients with social phobia: comparison to patients with panic disorder and healthy volunteers. 2002b Stein DJ. 2000 [PubMed] Spiegel DA. Psychosom Med 52:129–142. Muller N. Graff E. Lydiard B. 2001b Stein MB. et al: Full and partial posttraumatic stress disorder: findings from a community survey. Psychiatry Res 81:283–291. 2001a Stein MB. Arch Gen Psychiatry 58:251–258. Hami S. Liebowitz MR. Am J Psychiatry 157:1606–1613. Goldin PR. Pitts CD. Am J Psychiatry 154:1114–1119. Arch Gen Psychiatry 59:1111–1118. Delaney SM. J Child Psychol Psychiatry 41:713–762. 2003 [PubMed] Stapleton JA. Fyer AJ. et al: Irregular breathing during sleep in patients with panic disorder. Chartier MJ. Chartier M. Anderson G. 1994 [PubMed] Stein MB. 2002a Stein DJ. et al: Efficacy of paroxetine for relapse prevention in social anxiety disorder: a 24 week study. Am J Psychiatry 156:756–760. Davidson JRT. 1995b Stein MB. Stein MB. 1998a Stein MB. placebo-controlled study. Bruce TJ. 1995 [PubMed] Stein DJ. with and without parental involvement. Seedat S: Pharmacotherapy for post traumatic stress disorder. Am J Psychiatry 153:275–277. 1996 [Full Text] [PubMed] Stein MB. Asmundson GJ: Autonomic function in panic disorder: cardiorespiratory and plasma catecholamine responsivity to multiple challenges of the autonomic nervous system.

Am J Psychiatry 161:1049–1056. Pollack MH. Neuroimage 29:125–135. et al: A randomized trial of cognitive therapy and imaginal exposure in the treatment of chronic posttraumatic stress disorder. Nordera G. Kellner M. pp 269–288 Swedo SE. Kolassa IT. J Clin Psychiatry 64:250–258. Biol Psychiatry 45:321–326. Leonard HL. Stein MB. et al: Effects of cognitive behavioral therapy on brain activation in specific phobia. 1995 [PubMed] Stocchi F. Schapiro MB. et al: Efficacy and tolerability of paroxetine for the long-term treatment of generalized anxiety disorder. et al: Brain structural abnormalities in psychotropic drug naïve pediatric patients with obsessive compulsive disorder. et al: Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder. Bystritsky A. 1999 [PubMed] Swedo SE: Rituals and releasers: an ethological model of obsessive-compulsive disorder. 2004 [Full Text] [PubMed] Szeszko PR. Arch Gen Psychiatry 62:782–790. Glauer M. Arch Gen Psychiatry 46:335–341. McMeniman M. Alvir JM. Biol Psychiatry 56:921–930. J Consult Clin Psychol 67:13–18. Edited by Rapoport phobia. Pietrini P. 2004 [PubMed] Straube T. American Psychiatric Press. Cheslow DL. Jokinen RH. 1992b Szeszko PR. Psychopharmacol (Berl) 177:280–288. Ardekani BA. DC. 2003 [PubMed] Taylor FB. et al: Efficacy of low and higher dose extended-release venlafaxine in generalized social anxiety disorder: a 6-month randomized controlled trial. Olympia J: Divalproex in posttraumatic stress disorder (letter). 2006 [PubMed] Strohle A. 2002 [PubMed] Stein MB. 1989b Swedo SE. et al: White matter abnormalities in obsessive compulsive disorder: a diffusion tensor imaging study. Washington. Rapoport JL. Ashtari M. Turner SM. et al: Social phobia: an analysis of possible developmental factors. Anxiety 1:216–223. in Obsessive-Compulsive Disorder in Children and Adolescents. 1989a Swedo SE. et al: Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder: revisualization during pharmacotherapy. Holsboer F. J Clin Psychiatry 64:1421–1425. Uhde TW: Growth hormone response to intravenous clonidine in social phobia: comparison to patients with panic disorder and healthy volunteers. 1989c Swedo SE. Am J Psychiatry 148:1086–1087. Leonard H. Sommerfield C. Raskind MA: The alpha1-adrenergic antagonist prazosin improves sleep and nightmares in civilian trauma . Biol Psychiatry 34:591–595. Clark DM: Social phobia and interpretation of social events. 2000 [PubMed] Straube T. et al: Neuroendocrine responsivity to monoaminergic system probes in generalized social phobia. 2005 [PubMed] Szymanski HV. et al: Orbital frontal and amygdala volume reductions in obsessive-compulsive disorder. Glauer M. and cardiovascular response to flumazenil: no evidence for an altered benzodiazepine receptor sensitivity in panic disorder. Stein MB. Arch Gen Psychiatry 56:913–919. Arch Gen Psychiatry 49:29–36. neuroendocrine. Beidel DC. Arch Gen Psychiatry 46:518–523. Rapoport JL. Grady CL. Mailman RB. Kruesi MJP. Behav Res Ther 38:273–283. Arch Gen Psychiatry 49:690–694. Leonard HL. 1989. 1993 [PubMed] Tancer ME. Pilgrim H. 1992a Swedo SE. 1999 [PubMed] Szeszko PR. et al: Effect of task conditions on brain responses to threatening faces in social phobics: an event-related functional magnetic resonance imaging study. 2005 [PubMed] Stemberger RT. Arch Gen Psychiatry 59:1027–1034. 1994 [PubMed] Tarrier N. Dilger S. 1991 [PubMed] Tancer ME. 1999 [PubMed] Taylor FB: Tiagabine for posttraumatic stress disorder: a case series of 7 women. 2003 [PubMed] Stopa L. et al: Increased incidence of obsessive-compulsive symptoms in patients with Sydenham's chorea. et al: Obsessive-compulsive disorder in children and adolescents: clinical phenomenology of 70 consecutive cases. J Abnorm Psychol 104:526–531. Am J Psychiatry 146:246–249. MacMillan S. et al: Cerebrospinal fluid neurochemistry in children and adolescents with obsessive-compulsive disorder. Robinson D. et al: Behavioral.

et al: Behavior therapy augments response of patients with obsessive compulsive disorder responding to drug treatment. Arch Gen Psychiatry 51:559–567. Walker JR. et al: Sertraline treatment of generalized social phobia: a 20-week. Marteinsdottir I. J Affect Disord 30:155–161. 1992 [PubMed] Van Ameringen M. Acta Psychiatr Scand 87:456–462. Castro CC. 1994 [PubMed] Ursano RJ. 2002 [PubMed] Taylor 22-year follow-up study. Am J Psychiatry 156:589–595. Epstein RS. 1994 [PubMed] Torgersen S: Genetic factors in anxiety disorders. Beidel DC. Ducrocq F. 2006 [PubMed] Taylor S. Lane RM. 1997a Tiihonen J. Kuikka J. Marcos T. Lowe K. 2004 [PubMed] Tollefson GD. a PET study. Furmark T. 2001a Tillfors M. Streiner DL: Fluoxetine efficacy in social phobia. Cooley-Quille MR: Two-year follow-up of social phobias treated with social effectiveness therapy. 2005 [PubMed] Vallejo J. et al: Normal urinary free cortisol and postdexamethasone cortisol in social phobia: comparison to normal volunteers. Agras WG. Arch Gen Psychiatry 50:257–264. 1993 [PubMed] Thorgeirsson TE. J Clin Psychiatry 66:1169–1175. Am J Psychiatry 154:239–242. 2006 [PubMed] Turner SM. Miguel EC. Denys DA. Taylor CM. double- . Arch Gen Psychiatry 40:1085–1089. et al: A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. et al: Low posttrauma GABA plasma levels as a predictive factor in the development of acute posttraumatic stress disorder. 2005 [PubMed] Thomsen PH. 2004 [PubMed] Valente AA Jr. Diefenback GJ. Biol Psychiatry 59:523–529. 2003 [PubMed] Tiihonen J. Thompson C. Thomas P. 2001b Tolin DF. Mol Psychiatry 2:463–471. et al: Acute and chronic posttraumatic stress disorder in motor vehicle accident victims. van Megen HJ. Mikkelsen HU: Development of personality disorders in children and adolescents with obsessivecompulsive disorder: a 6. Biol Psychiatry 58:479–487. Br J Psychiatry 161:665–670. 2005 [PubMed] Telch MJ. Desnica N. Tancer ME. Kuikka J. Olivares J. DeBellis MD: Segmented hippocampal volume in children and adolescents with posttraumatic stress disorder.posttraumatic stress disorder. Maltby N. 1997b Tillfors M. 1983 [PubMed] True WR. et al: Cerebral benzodiazepine receptor binding and distribution in generalized anxiety: a fractal analysis. Behav Res Ther 23:325–335. et al: Social phobia and avoidant personality disorder as related to parental history of social anxiety: a general population study. J Clin Psychiatry 54:27–32. J Clin Psychiatry 65:922–931. Abramowitz JS: Hierarchical structure of dysfunctional beliefs in obsessive compulsive disorder: Cogn Behav Ther 34:216–228. et al: Combined pharmacological and behavioral treatment for agoraphobia. et al: Daytime prazosin reduces psychological distress to trauma specific cues in civilian trauma posttraumatic stress disorder. et al: A multicenter investigation of fixed-dose fluoxetine in the treatment of obsessive-compulsive disorder. McKay D. Bergstrom K. 1985 [PubMed] Tenneij NH. Ekselius L. Gelernter CS. Behav Res Ther 39:289–298. Fullerton CS. 1993 [PubMed] Tupler LA. Rampey AH. Am J Psychiatry 158:1220–1226. et al: Anxiety with panic disorder linked to chromosome 9q in Iceland. Oskarsson H. 1993 Van Ameringen MA. Biol Psychiatry 55:250–254. Rice J. Am J Hum Genet 72:1221–1230. 1999 [Full Text] [PubMed] Vaiva G. et al: Dopamine reuptake site densities in patients with social phobia. Mancini C. Biol Psychiatry 59:577–581. Eisen SA. J Clin Psychopharmacol 22:82–85. 1995 [PubMed] Uhde TW. Potvin JH. et al: Cognitive behavioral therapy for medication nonresponders with obsessive compulsive disorder: a wait list controlled open trial. Furmark T. Rasanen P. et al: Regional gray matter abnormalities in obsessive compulsive disorder: a voxel based morphometry study. Behav Res Ther 33:553–555. et al: Cerebral blood flow in subjects with social phobia during stressful speaking tasks. et al: Clomipramine versus phenelzine in obsessive-compulsive disorder: a controlled clinical trial.

et al: Long term treatment with paroxetine increases verbal declarative . panic disorder. Groenewegen HJ. Washington. 1987a. pp 123–134 van der Kolk BA. Washington. et al: An open trial of topiramate in the treatment of generalized social phobia. and masochism. Boyd H. Vythilingam M. Psychiatry Res 132:13–18. Patterson B. Huygens K. et al: Functional brain imaging and pharmacotherapy in social phobia: single photon emission computed tomography before and after treatment with the selective serotonin reuptake inhibitor citalopram. J Clin Psychiatry 58:164–168. van Balkom AJ. 1994 van Vliet IM. pp 31–62 van der Kolk BA: The compulsion to repeat the trauma: reenactment. open label case series. den Boer JA. et al: Topiramate augmentation in treatment resistant obsessive compulsive disorder: a retrospective. van der Hart O: Pierre Janet and the breakdown of adaptation in psychological trauma. in Psychological Trauma. et al: Post-traumatic stress disorder as a biologically based disorder: implications of the animal model of inescapable shock. Szechtman H. Depress Anxiety 23:1–5. Veltman DJ. in Psychological Trauma. J Clin Psychiatry 66:1415–1422. 2006 van den Heuvel OA. Edited by van der Kolk BA. American Psychiatric Press. de Haan E. J Clin Psychiatry 65:1674–1678. Southwick SM.blind. 1995 van Oppen P. Dreyfuss D. et al: Cognitive therapy and exposure in vivo in the treatment of obsessive compulsive disorder. Tenney N. Edited by van der Kolk BA. 2005b Van Den Hout M. Behav Res Ther 35:29–34. Mancini C. pp 153–171 van der Kolk BA: The separation cry and the trauma response: developmental issues in the psychobiology of attachment and separation. Hosp Community Psychiatry 34:683–691. and hypochondriasis. Am J Psychiatry 146:1530–1540. 1989 van der Kolk BA. Veltman DJ. DC. revictimization. 2000 van Oppen P. Westenberg HGM. 2005a van den Heuvel OA. et al: Frontal striatal dysfunction during planning in obsessive compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry 24:419–438. 2004c Van Ameringen M. 1984. J Clin Psychopharmacol 24:42–48. 2004b Van Ameringen M. 2004a Van Ameringen M. Pipe B. et al: Clinical effects of buspirone in social phobia: a double-blind placebo-controlled study. Mancini C. Anxiety Res 4:199–212. Am J Psychiatry 158:275–281. 1997 Vermetten E. Krystal J. Saporta J: The biological response to psychic trauma: mechanisms and treatment of intrusion and numbing. Mancini C. Edited by van der Kolk BA. Arch Gen Psychiatry 62:301–309. 1991 van der Kolk BA. Washington. American Psychiatric Press. Westenberg HG: Psychopharmacological treatment of social phobia: a double blind placebo controlled study with fluvoxamine. Oakman J. 1989 van der Kolk BA. Arch Gen Psychiatry 62:922–933. Psychopharmacol (Berl) 115:128–134. 1994 Van Der Linden G. Michaels M. American Psychiatric Press. placebo-controlled study. DC. 1997 van der Kolk BA: Psychopharmacological issues in posttraumatic stress disorder. et al: A PET provocation study of generalized social phobia. et al: Cognitive therapy and exposure in vivo alone and in combination with fluvoxamine in obsessive compulsive disorder: a 5 year follow up. DC. Psychiatr Clin North Am 12:389–411. Warwick J. et al: Preconscious processing bias in specific phobia. van Balkom AJ. van-Heerden B. et al: Fluoxetine in posttraumatic stress disorder. Mancini C. 2005 van Vliet IM. et al: Disorder-specific neuroanatomical correlates of attentional bias in obsessive-compulsive disorder. de Haan E. in Post-Traumatic Stress Disorder: Psychological and Biological Sequelae. 2001 Van Ameringen M. 1983 van der Kolk BA: The role of the group in the origin and resolution of the trauma response. Groenewegen HJ. den Boer JA. 1987b. J Clin Psychiatry 55:517–522. et al: Predictors of response in generalized social phobia: effect of age of onset. Behav Res Ther 33:379–390.

1878 Whittal ML. et al: Disabilities and quality of life in pure and comorbid generalized anxiety disorder and major depression in a national survey. DC. Lambert GW. Yoa Shugart Y. Arch Psychiatr Neurol 8:734–750. fixed dose study. 1999 [PubMed] Westphal K: Ueber Zwangsverstellungen [obsessional thoughts]. pp 327–344 Wittchen HU. Noyes R. Irle E: Hippocampal volume in adult burn patients with and without posttraumatic stress disorder. McLean PD. Westenberg HG: Bupropion for patients with obsessive compulsive disorder: an open label. et al: Exposure in vivo vs social skills training for social phobia: long-term outcome and differential effects. Keller MB: Suicidal behavior in patients with current or past panic disorder: five years of prospective data from the Harvard/Brown Anxiety Research Program. et al: Treatment of obsessive compulsive disorder: cognitive behavior therapy vs. J Clin Psychiatry 66:228–230. Carter RM. Denys D. Behav Res Ther 43:1559–1576. Am J Psychiatry 156:1223–1229. 1998 [PubMed] Warshaw MG. 1989. Hand I. J Clin Psychopharmacol 8:279–283. Alden LE: Social phobia and positive social events: the price of success. et al: DSM-III-R generalized anxiety disorder in the National Comorbidity Survey. Pfister H. 2005 [PubMed] Wade AG. Arch Gen Psychiatry 55:511–520. 1997 [PubMed] Wang Z. 2004 [PubMed] Vulink NC. 2003 [PubMed] Wallace ST. Biol Psychiatry 54:693–702. et al: Replication study supports evidence for linkage to 9p24 in obsessive compulsive disorder. Rapoport JL: Obsessive-compulsive disorder: is it a basal ganglia dysfunction? in Obsessive-Compulsive Disorder in Children and Adolescents. Am J Med Genet 81:228–234. Alavi A. clinical and EEG findings: possible . J Abnorm Psychol 113:582–591. Br J Psychiatry 170:549–553. 2005 [PubMed] Wiborg IM. Behav Res Ther 37:585–594. McNally RJ: Panic disorder and suicide attempt in the National Comorbidity Survey. Dahl AA: Does brief dynamic psychotherapy reduce the relapse rate of panic disorder? Arch Gen Psychiatry 53:689–694. 1999 [Full Text] [PubMed] Wilkinson DJ. et al: Tranylcypromine in social phobia. 2003 [PubMed] Versiani M. Samuels J. 2004 [Full Text] [PubMed] Wise SP. 1990 [PubMed] Wells A. Lepola U. Markowitz JS. Schroeder-Hartwig K. Thompson JM. Behav Res Ther 28:181–193. 2000 [Full Text] [PubMed] Weissman MM. and during panic attacks. Int Clin Psychopharmacol 15:319–328. 1997 [PubMed] Wald J. Arch Gen Psychiatry 51:355–364. et al: Possible association of a cholecystokinin promoter polymorphism (CCK-36CT) with panic disorder. Am J Psychiatry 147:1504–1508. Ouellette R. under laboratory mental stress. 1988 [PubMed] Vickers K. 1990 [PubMed] Wolf ME. 2000 [PubMed] Wlazlo Z. Nardi AE. J Abnorm Psychol 106:416–424. Cyberpsychol Behav 6:459–465. Edited by Rapoport JL. Thordarson DS. Carter K: Preliminary tests of a cognitive model of generalized anxiety disorder. Am J Psychiatry 157:1876–1878. Kessler RC. et al: Sympathetic activity in patients with panic disorder at rest. 2004 [PubMed] Winter H. Washington. Dolan RT. Koponen HJ. Mundim FD. 1994 [PubMed] Wittchen HU. et al: Panic disorder and cardiovascular/cerebrovascular problems: results from a community survey. Am J Hum Genet 75:508–513. et al: The effect of citalopram in panic disorder. Am J Psychiatry 161:2194–2200. Taylor S: Preliminary research on the efficacy of virtual reality exposure therapy to treat driving phobia. Valdes J.memory and hippocampal volume in posttraumatic stress disorder. Mosnaim AD: Posttraumatic stress disorder in Vietnam veterans. 1998 [PubMed] Willour VL. 1996 [PubMed] Widom CS: Posttraumatic stress disorder in abused and neglected children grown up. exposure and response prevention. Zhao S. American Psychiatric Press.

J Psychopharmacol 19:551–553. 2004a Young EA. et al: Vulnerability to posttraumatic stress disorder in adult offspring of Holocaust survivors. 2006 [PubMed] Yonkers KA. 1988 [PubMed] Woo JM. Breslau N: Cortisol and catecholamines in posttraumatic stress disorder: an epidemiologic community study. Biol Psychiatry 56:205–209. J Clin Psychiatry 55:134–136. 2005b Zatzick DF. 2006 [PubMed] Woody SR. Arnold P. Chambless DL. J Nerv Ment Dis 187:3–9. Choi YH. 2005 [PubMed] Zimmerman M. et al: Dose-response changes in plasma cortisol and lymphocyte glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic stress disorder. Marmar CR. et al: PET in generalized anxiety disorder. Am J Psychiatry 154:1690–1695. et al: Reevaluating the association between emergency department heart rate and the development of posttraumatic stress disorder: a public health approach. Yoon KS. et al: Putaminal gray matter volume decrease in panic disorder: an optimized voxel-based morphometry study. Glass CR: Self-focused attention in the treatment of social phobia. et al: A 5-year follow-up study of generalized anxiety disorder and panic disorder. Psychiatr Genet 15:235. 1998b Yehuda R. World Health Organization. Yoon KS. Russo J. Weiss DS. Br J Psychiatry 168:308–313. Black DW. Noyes R. 1994 [PubMed] Woodman CL. 1991 [PubMed] Yehuda R. Biol Psychiatry 59:582–587. Kaloupek DG. Davidson JR: Levetiracetam in social phobia: a placebo controlled pilot study. et al: The association between panic disorder and the L/L genotype of catecholO-methyltransferase. Eur J Neurosci 22:2089–2094. Breslau N: Saliva cortisol in posttraumatic stress disorder: a community epidemiologic study. Connor KM. 2005 [PubMed] Young EA. Wainberg M. Behav Res Ther 35:117–129. 1999 [PubMed] Woodward SH. 10th Revision (ICD-10). 1992 Wu JC. Boisoneau D.therapeutic effects of carbamazepine. Kim SJ. 1996 [PubMed] Yoo HK. Kim MJ. Pitman RK. J Psychiatr Res 38:365–370. Arnold P. Am J Psychiatry 155:1163–1171. Streeter CC. 2002 [Full Text] [PubMed] Woo JM. Warshaw MG. 1997 [PubMed] World Health Organization: International Statistical Classification of Diseases and Related Health Problems. Shalev AY: Predicting the development of posttraumatic stress disorder from the acute response to a traumatic event. Buchsbaum MS. and coping. Biol Psychiatry 59:660–663. et al: Phenomenology and course of generalised anxiety disorder. et al: No association between brain derived neurotrophic factor gene and obsessive compulsive disorder. Brand S. Burroughs E. 2005a Zai G. Arch Gen Psychiatry 61:394–401. Yu BH: Catechol-O-methyltransferase genetic polymorphism in panic disorder. Am J Med Genet B Neuropsychiatr Genet 134:25–29. 2005 [PubMed] Zhang W. Hershey TG. Biol Psychiatry 29:1181–1199. 1995 [PubMed] Yehuda R. Biol Psychiatry 44:1305–1313. Lowy MT. recovery from PTSD. McFarlane AC. Schmeidler J. Biol Psychiatry 23:642–644. Arch Gen Psychiatry 52:583–593. Am J Psychiatry 159:1785–1787. Switzerland. et al: Posttraumatic stress disorder and functioning and quality of life outcomes in a nationally representative sample of male Vietnam veterans. et al: Evidence for the gamma-aminobutyric acid type B receptor 1 (GABBR1) gene as a susceptibility factor in obsessive compulsive disorder. Massion AO. 1997 [Full Text] [PubMed] Zatzick DF. Geneva. Biol Psychiatry 57:91–95. Noyes R: Panic disorder: treatment with valproate. Strauss J. 1998a Yehuda R. 2004b Zai G. et al: Decreased anterior cingulated volume in combat related PTSD. Yang RK: Plasma neuropeptide Y concentration in combat exposed veterans: relationship to trauma exposure. Chelminski I: Generalized anxiety disorder in patients with major depression: is DSM-IV's hierarchy . 2004 [PubMed] Woodman CL.

Insel TR. 1997 [PubMed] Zlotnick C. et al: Chronicity in posttraumatic stress disorder (PTSD) and predictors of course of comorbid PTSD in patients with anxiety disorders. Warshaw M. Inc. J Trauma Stress 12:89–100. 1980 [PubMed] Zlotnick C. Arch Gen Psychiatry 37:63–72. Zohar-Kadouch RC. et al: Serotonergic responsivity in obsessive-compulsive disorder: effects of chronic clomipramine treatment. 1999 [PubMed] Zohar J. All Rights Reserved. J Trauma Stress 10:425–436. Shea TM. et al: An affect-management group for women with posttraumatic stress disorder and histories of childhood sexual abuse.correct? Am J Psychiatry 160:504–512. Arch Gen Psychiatry 45:167–172. Rosen K. Shea MT. 1988 [PubMed] Copyright © 2010 American Psychiatric Publishing. . Woerner MG: Treatment of agoraphobia with group exposure in vivo and imipramine. Klein DF. 2003 [Full Text] [PubMed] Zitrin CM.

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