Daniel

Overview Clinical challenges in the diagnosis and treatment of anxiety are abundant in the general hospital setting: discerning normal from pathologic anxiety, differentiating medical from psychiatric causes, and choosing effective therapeutic approaches. In addition to a knowledge of medical and psychiatric differential diagnoses, the clinician may rely on a variety of strategies and interventions that involve pharmacologic, cognitive-behavioral, interpersonal, and psychodynamic skills. The ubiquity of anxiety and the non-specific nature of anxiety symptoms can confound the care of the patient. Pathologic anxiety symptoms and behavior may be attributed to other physical causes or, when viewed as “only anxiety,” may be prematurely dismissed as insignificant. Anxiety refers to a state of anticipation of alarming future events, whereas fear is a result of perceived imminent threat.1 The former is the same distressing experience of dread and foreboding as the latter, except that it derives from an unknown internal stimulus or is inappropriate to the reality of the current situation. Anxiety is manifested in the physical, affective, cognitive, and behavioral domains. The possible physical symptoms of anxiety reflect autonomic arousal and include an array of bodily perturbations (Table 13-1). The anxious state ranges from edginess and unease to terror and panic. Cognitively, the experience is one of worry, apprehension, and thoughts concerned with emotional or bodily danger. Behaviorally, anxiety triggers a multitude of responses concerned with diminishing or avoiding the distress. Table 13-1 Physical Signs and Symptoms of Anxiety Anorexia “Butterflies” in stomach Chest pain or tightness Diaphoresis Diarrhea Dizziness Dry mouth Dyspnea Faintness 381 Flushing Headache Hyperventilation Light-headedness Muscle tension Nausea Pallor Palpitations Paresthesias Sexual dysfunction Shortness of breath Stomach pain Tachycardia Tremulousness Urinary frequency Vomiting The importance of recognizing and attending to the suffering of the anxious patient is not always readily apparent, given the universality of the experience of anxiety. Anxiety is expected and normal as a transient response to stress and may be a necessary cue for adaptation and coping. Excessive or pathologic anxiety, however, is no more a normal state than is the production of excess thyroid hormone. Pathologic anxiety is distinguished from a normal emotional response by four criteria: autonomy, intensity, duration, and behavior. Autonomy refers to suffering that, to some extent, has a life of its own, with a minimal basis in recognizable environmental stimuli. Intensity refers to the level of distress; the severity of symptoms is such that the patient's level of anguish moves the physician to offer relief. The duration of suffering also can define anxiety as pathologic. Symptoms that are persistent rather than transient, possibly adaptive, indicate a disorder and they are a call to evaluation and treatment. Finally, behavior is a critical criterion; if anxiety impairs coping, if normal function is disrupted, or if behavior such as avoidance or withdrawal results, 382 the anxiety is of a pathologic nature. Stereotyped syndromes of pathologic anxiety are described in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM).2 Changes in the DSM-5 diagnostic criteria for anxiety disorders include the re-categorization of obsessive–compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and acute stress disorder. These syndromes will all be included in this chapter given the pervasiveness of anxiety and fear that is common to all of these disorders. In epidemiologic studies, anxiety disorders have been found to be among the most common psychiatric disorders in the general population.3 This observation predicts that a significant percentage of the general hospital population would also suffer from anxiety symptoms. Some patients suffer from an anxiety disorder before admission to the hospital for medical care, but medical and surgical settings are also associated with the onset of anxiety symptoms as a consequence of hospitalization, medical illness, or treatment (e.g., adjustment disorder with anxious mood and organic anxiety disorder).4 383 The Nature and Origin of Anxiety Despite the protean physiologic manifestations of anxiety, the experience of anxiety can be divided into two broad categories: (1) an acute, severe, and brief wave of intense anxiety with impressive cognitive, physiologic, and behavioral components, and (2) a lower-grade persistent distress, quantitatively distinct and also with some qualitative differences. Pharmacologic and epidemiologic observations suggest a clinically relevant distinction between these two states. In light of phenomenologic similarities, fear and anxiety most likely reflect a common underlying neurophysiology. The first category of anxiety resembles acute fear or alarm in response to life-threatening danger: a cognitive state of terror, helplessness, or sense of impending disaster or doom, with autonomic but primarily sympathetic activation, and an urgency to flee or seek safety. The second type of anxiety corresponds to a state of alertness with a heightened sense of vigilance to possible threats and with less intense levels of inhibition, physical distress, and behavioral impairment. The two fear states resemble the clinical syndromes of panic attacks and generalized or anticipatory anxiety. As innate responses for protecting the organism and enhancing survival, panic and vigilance are normal when faced with threatening stimuli. As anxiety or psychopathologic symptoms, other factors besides actual physical threat must be implicated as triggers or causes. Of several explanatory models proposed, the biological model places emphasis on the nervous system, the psychodynamic on meanings and memories, and the behavioral on learning. Animal and neuronal receptor studies suggest that a number of central systems are involved in fear and pathologic anxiety.5,6 The alarm or panic mechanism is likely to have a critical component involving central noradrenergic mechanisms, with particular importance placed on a small retropontine nucleus, the primary source of the brain's norepinephrine, the locus ceruleus (LC). When this key to sympathetic activation is stimulated in monkeys, for example, an acute fear response can be elicited with distress vocalizations, fear behaviors, and flight. Furthermore, destruction of the LC leads to abnormal complacency in the face of threat.7 Biochemical perturbations that increase LC firing similarly elicit anxious responses in animals and humans that are blocked by agents that decrease LC firing, some of which are in clinical practice as anti-panic agents (e.g., antidepressants, alprazolam).8 Another critical system involves limbic system structures, including the amygdala and septohippocampal areas. An important role of the limbic system is to scan the environment for life-supporting and life-threatening cues, as well as to monitor internal or bodily sensations, and to integrate these with memory and cognitive inputs in assessing the degree of threat and need for action to maintain safety.9 Vigilance, or its psychopathologic equivalent, generalized anxiety, most probably involves limbic system activity: limbic alert. Benzodiazepine receptors in high concentrations in relevant limbic system structures may play a role in 384 modulating limbic alert, arousal, and behavioral inhibition10 by increased binding of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).11 As one might expect, there are neuronal connections between the LC and the limbic system. An increased firing rate of LC neurons may serve as a rheostat to generate levels of arousal from vigilance to alarm. A number of neurotransmitters are implicated as modulators of both the limbic alert and the central alarm systems. For example, LC firing is regulated by the α2-noradrenergic autoreceptors as well as by 5-hydroxytryptamine (5- HT), serotonin receptors, GABA-benzodiazepine receptors, and opioid and other receptors. The limbic system also has important GABA-benzodiazepine receptor and serotonergic modulations. Peptides, such as cholecystokinin,12 have also been implicated as potential activators of the alarm system, and an accruing body of work points to abnormalities in corticotropin-releasing factor and hypothalamic–pituitary axis function as critical in the genesis and maintenance of pathologic affective states.13 As a critical function, the central security system is endowed with redundancy of regulation. When inappropriately activated, vigilance and alarm (the stereotyped functions of the security system) are manifested as psychopathology: anxiety states. The more sustained, variably intense, but distressing arousal state of vigilance (i.e., preparation for threat) becomes generalized anxiety. The sudden, stereotyped, and intense (but false) alarm response is a panic attack. Cognitive-behavioral formulations of anxiety disorders, although attending to possible differences in biological reactivity, focus primary attention on the information processing and behavioral reactions that characterize an individual's anxiety experience. Although anxiety patterns may stem from a variety of experiences, including (mis)information, observational learning, and direct conditioning events with real or perceived trauma, the enduring consequences of such learning can be found in current patterns of behavior. In cognitive-behavioral formulations, emphasis is placed on the role of thoughts and beliefs (cognitions) in activating anxiety, as well as on the role of avoidance or other escape responses in maintaining both fear and faulty thinking patterns. Faulty cognitions are frequently marked by the over-prediction of the likelihood or degree of catastrophe of negative events and may focus on external experiences (e.g., “my colleagues will laugh at me if I ask this question”) or internal experiences (e.g., “I am going to lose control if this anxiety gets worse”). Intolerance and catastrophic misinterpretations of the anxiety experience itself play a role in a variety of anxiety conditions and can help propel mild anxiety into a full, intense panic attack. Attempts to neutralize anxious feelings, with avoidance or compulsive behavior, can serve to lock in anxiety reactions and help to develop the chronic arousal and anticipatory anxiety that marks many anxiety disorders. Recent evidence has offered a bridge between neurobiological and cognitivebehavioral understandings of anxiety. Increased attention has been paid to the consolidation of memories after traumatic experiences and potential therapeutic interventions (e.g., blocking of the noradrenergic or glucocorticoid systems to decrease the potential for developing PTSD after trauma). Knowledge of the N- 385 methyl-D-aspartate (NMDA) system's involvement in the extinction of learned behaviors has offered the possibility of pharmacologic enhancement of cognitive-behavioral therapy (CBT) techniques. D-cycloserine, a partial NMDA agonist, has facilitated treatment of specific phobias, obsessive–compulsive disorder (OCD), panic disorder, and social anxiety disorders when combined with CBT.14 Developmental experiences receive particular emphasis in psychodynamic approaches to anxiety. Although Freud's early writing implied a more physiologic basis for anxiety attacks in terms of undischarged libido, later emphasis was on anxiety as a signal of threat to the ego, signals elicited because of events and situations with similarities (symbolic or actual) to early developmental experiences that were threatening to the vulnerable child (traumatic anxiety), such as separations, losses, certain constellations of relationships, and symbolic objects or events (e.g., snakes, successes). More recently, psychodynamic thinking has emphasized object relations and the use of internalized objects to maintain affective stability under stress. Phobic disorders, associated with the experience of panic, anticipatory anxiety, or no anxiety symptoms at all (depending on the success of avoidance behavior), serve to illustrate the different models of understanding anxiety. The biological view recognizes the stereotyped nature of phobias. Most of the objects and situations in everyday life that truly threaten us are rarely selected as phobic stimuli; children, who proceed normally through a variety of developmental phobias (e.g., strangers, separation, darkness), rarely become phobic of objects and situations that parents attempt to associate with danger (e.g., electric outlets and roads), and most phobic stimuli have meaning in the context of biological preparedness and were presumably selected through evolution.15 Most human phobias are of objects and situations that make sense in the context of enhancing survival before the dawn of civilization: places of restricted escape, groups of strangers, heights, and snakes, for example. Social phobias—for example, fear of scrutiny by others—resemble the intense discomfort elicited in primates introduced into a new colony or in any animal simply being stared at. A glare is a threat. When panic attacks and anticipatory anxiety heighten the general sense of danger and insecurity, a variety of phobias may be manifested as part of the patient's increased concern with security and safety. The principal explanatory models in psychiatry of how a normal protective system might become the source of distress and dysfunction include the biological (with its emphasis on constitutional vulnerability), the cognitivebehavioral (with its emphasis on self-perpetuating patterns of cognitions and behaviors), and the psychodynamic (with its emphasis on meanings, memories, and internal representations derived from developmental experience). The pragmatic and pluralistic modern clinician should not regard these models as mutually exclusive. Potential biological vulnerabilities, for example, may never become manifest without specific developmental experiences, sustained adversity, or trauma. Accumulating evidence indicates that for anxiety disorders, as with affective and psychotic disorders, biological systems are 386 responsive to, and perturbable by, environmental influences. Potentially dysregulated (i.e., anxiety-prone) neurobiological systems may remain homeostatic until developmental experience, life events, or other stressors disturb them. An integrated model predicts risk for manifested anxiety disorders as a consequence of constitutional vulnerability shaped by developmental experience (whether harmful or protective) and, in later (adult) life, either activated or influenced by environmental factors and maintained by ongoing chains of maladaptive cognitions and avoidance responses. 387 Anxiety in the Medical Setting Although some distress from anxiety is expected as a routine consequence of hospitalization, anxiety may also be a significant clinical issue in the treatment of patients in a medical setting. The hospitalized patient encounters a world of both internal and external dangers: assaults on bodily integrity in the form of uncomfortable procedures and forced intimacy with strangers; the atmosphere of illness, pain, and death; and separation from loved ones and familiar surroundings. The patient typically experiences uncertainty about his or her illness and its implications for the patient's capacity to work and maintain social and family relationships. Just as depression has been described as a “psychobiological final common pathway” of a number of interacting determinants,16 it is likely that anxiety too represents a multiple-determined expression of the variety of psychological, biological, and social factors having impact on the patient. The anxious patient can be a diagnostic challenge. The presence of anxiety may represent the patient's reaction to the meaning and implications of medical illness or to the medical setting, a manifestation of the physical disorder itself, or the expression of an underlying psychiatric disorder. The distinction between anxiety as a symptom and anxiety as a syndrome, may be difficult to make in the medical setting, where there may be an overlap between normal situational anxiety or fear, anxiety-like symptoms resulting from a variety of organic disease states and their treatments, and the characteristic presentation of anxiety disorders. Methodological obstacles surface in attempts to identify the nature and prevalence of anxiety in medical patients.17 Studies of anxiety in the medical setting are often difficult to interpret because of a lack of clarity of case definition and assessment measures, heterogeneity of the study populations, absence of appropriate control groups, and the non-specific and often transitory nature of the anxiety symptoms themselves. Approximately 60% of patients with psychiatric conditions are treated by primary care practitioners; the most common disorders are depression and anxiety.18,19 In a study of patients who presented to a group of primary care physicians, anxiety was the fifth most common diagnosis overall; others suggest this may be an underestimate.20,21 Anxiety is the chief complaint of 11% of patients presenting in primary care settings.22 This prevalence is mirrored by the high rate of prescribing benzodiazepines by primary care physicians.23 Panic disorder has a reported prevalence of 1% to 2% in the general population,24 as compared with 6% to 10% of patients in a primary care setting25 and 10% to 14% of patients in a cardiology practice.26 Patients with anxiety disorders, furthermore, are but a subgroup of those for whom anxiety is a complicating factor in their diagnosis and treatment in the hospital. In view of the likely frequency of normal anxiety in this setting, there must be special circumstances surrounding those patients identified by primary caregivers as deserving psychiatric attention. Although some overly anxious 388 patients go unrecognized, those who generate concern have impressed their caregivers in some way by the autonomy, intensity, duration, or behavior associated with their distress. Several typical scenarios of anxiety in the general hospital can be recognized. Anxiety From Failure to Cope For most patients, potentially overwhelming stressors of hospitalization are mitigated by a variety of coping mechanisms. The sources of threat and the flood of perceptions signaling potential danger are managed by common strategies: rationalization and self-reassurance (“I've come this far,” “the doctors know what they're doing,” “safest place in the world”); denial and minimization (“the chest pain is just heartburn,” “these machines will protect me”); religious faith; support from family and friends; and other strategies determined by the patient's personality style. Even for those without a pre-illness anxiety disorder, coping strategies may fail and yield to a sense of fear and vulnerability. A host of factors may be implicated in this failure: personality features with brittleness or a tendency to regress in the face of threat (or paradoxically in a setting that evokes passivity and offers access to nurturance), the suddenness of the onset of threat (acute, life-threatening medical or surgical disease), unavailability of familial or other social support, feelings of aloneness or abandonment, or the unconscious meaning of the particular illness or injury. The patient becomes frightened, trembles, cannot sleep, repeatedly seeks attention and reassurance, registers excessive pain complaints and other physical symptoms, and becomes disruptive and unable to manage the fear. For many, especially the young or those with organic brain syndromes (e.g., mental retardation or dementia), catastrophic emotional responses are more readily triggered. Case 1 A psychiatric consultation request was received for a 17-year-old high school junior following an above-the-knee amputation for osteogenic sarcoma without evidence of metastasis at the time of surgery. He had returned to school with a prosthesis and had done well. Some months later, a pulmonary metastasis was discovered, and he was re-hospitalized for surgery and chemotherapy. Although anticipating a favorable outcome at this point, his behavior was unlike that of his prior hospitalization. He raged at caregivers, acted panicky, and withdrew from contact. Consultation was sought for treatment of his anxiety. He was a tall, handsome, athletic young man admired by his peers, a leader who managed his life with braggadocio and pseudo-independence. For the first time in his illness, he was overwhelmed and frightened. Two critical issues emerged from the interview. First, in the past, he had had a great deal of support from his peers, but lately he had refused their visits. He was embarrassed by hair loss from chemotherapy. Second, during this 389 hospitalization, his father, feeling overwhelmed by this turn of events, had decreased the frequency of visits to his son, claiming increased work demands. Two interventions calmed the acute anxiety. First, an effort was made to find a well-suited wig; second, a psychotherapeutic contact with the father helped him to manage his grief adequately to increase the frequency of visits, and thereby relieve his son's separation anxiety. Although the oncologist's request was for an anxiolytic prescription, recognition of the failure of coping ability yielded the appropriate therapy for the acute anxiety. This case serves to underscore two points: previously well-adapted individuals can become anxious in the face of serious or life-threatening illness; and, despite the appropriateness of anxiety in the face of serious illness, other factors, potentially remediable, may be involved in triggering anxious symptoms or behavior. In this case, troublesome behavior was evident; for others, only more subtle physical symptoms may have occurred. PTSD Resulting From Traumatic Procedures In recent years, increasing attention has been paid to the role of serious medical illness and invasive procedures in producing reactions that approach or meet criteria for PTSD. For example, symptoms of PTSD have been documented in patients after myocardial infarction (MI), coronary artery bypass graft surgery,27 and treatment for breast cancer,28 traumatic brain injury,29 and in those who require intensive care (a setting associated with increased morbidity and mortality).30 Estimates of rates of PTSD in these samples of patients range from 5% to 10%,28 with rates of PTSD in patients hospitalized after traumatic physical injuries as high as 30% to 40%.31 The emergence of PTSD is considered most likely when a traumatic event is perceived as both uncontrollable and lifethreatening32 as such, any attempts to help patients regain or maintain a sense of control over their experiences may prevent or reduce emergent distress. Case 2 Ms. B, a 52-year-old woman with a history of depression, anxiety, chronic back pain, and severe peripheral vascular disease, was admitted to the hospital as preparation for a femoral artery–popliteal artery bypass. Consultation was requested for management of anxiety because surgery had previously been attempted but was aborted when the patient became acutely anxious when the staff began to disrobe her. During the course of the consultation, Ms. B revealed that she had been the victim of a sexual assault at age 24. In the past, she had not needed treatment for symptoms related to this event. However, during the preparation for surgery, she began to re-experience her trauma while she was being disrobed. Education was provided to Ms. B regarding the sequence of events that would take place leading up to and during the operation. The surgical staff 390 was educated about the effects of past trauma and the need for special consideration regarding this patient. An agreement was made to allow the patient to disrobe herself prior to the initiation of the surgery. This increased her sense of control and she was able to tolerate the surgery, which went well. This case demonstrates the importance of the events that take place during a hospitalization, but also a patient's prior experiences with trauma. By talking with Ms. B and identifying the historical factors as well as the present conditions that made this experience difficult for her, a plan was devised to alleviate as much of her anxiety as possible. Under these conditions, she was able to take a more active role and complete the necessary medical procedure. Memory of events during anesthesia has been documented in controlled trials,33,34 leading to recommendations that the surgical staff provide reassurance to patients during surgery and monitor their own verbalizations in the presence of anesthetized patients. Intraoperative awareness occurs in 1–2 of every thousand cases and may occur with general anesthesia as well as with sedation/regional anesthesia.35 Risk factors for intraoperative awareness include use of light anesthesia (that is often used in conjunction with cardiac surgery, surgery following an acute trauma, and cesarean deliveries), and a history of intraoperative awareness.35 The modified Bruce interview is commonly used as a screening tool for the detection of intraoperative awareness.36 Intraoperative methods to reduce awareness of events include the use of monitoring end-tidal anesthetic concentration and the use of EEG-derived bispectral index to monitor levels of sedation.35 Both of these methods have proven effective at reducing rates of intraoperative awareness.37 Bispectral index is recommended when intravenous (IV) sedative–hypnotics or heterogeneous anesthetic agents are used primarily for sedation. End-tidal anesthetic gas concentration can be used if inhaled agents are utilized. Reactions to awareness during surgery include generalized anxiety and irritability, repetitive nightmares, and preoccupation with death, as well as reluctance to discuss the memory or associated symptoms.38 More severe reactions have also been documented, including the full emergence of PTSD after experiences of awareness during surgery. Rates of PTSD after intraoperative awareness have been reported to be as high as 70%.39 Patients who are aware during surgery may face the terrifying experience of pain occurring in conjunction with anesthesia-induced paralysis (ensuring that no overt coping or escape responses are available), and fear of death. As memories of the trauma emerge, patients may face the full spectrum of PTSD symptoms, including: re-experiencing symptoms (intrusive memories, nightmares, and over-responsivity to cues of the surgery); avoidance of reminders of the experience (e.g., avoidance of strong emotions, prone bodily positions or sleep, medical television shows, colors similar to those of surgical scrub suits); and symptoms of pervasive autonomic arousal (e.g., exaggerated startle, sleep difficulties, hypervigilance, and irritability). Timely identification of this syndrome can aid in rapid referral for full psychiatric evaluation and treatment, which may include both cognitive-behavioral and pharmacologic interventions. 391 Anxiety That Interferes With Evaluation or Treatment A request for consultation may be a consequence of anxiety that interferes with a patient's evaluation or treatment: refusal of work-up or treatment because of fear of pain or discomfort, catastrophic interpretation of physical symptoms or of the planned work-up (“they're looking for cancer”) with an excessively fearful response, or the need to minimize or deny a potentially serious condition and its implications, limiting cooperation with evaluation. Case 3 Examination of Mrs. C, a 38-year-old woman, revealed a large breast lump. Although initially reluctant, she eventually agreed to a mammogram. In the waiting room, she became increasingly anxious and, when her name was called, refused to come in for the test. A psychiatric consultation was called to provide management of the patient's anxiety to permit the mammogram. An attractive woman, she had stopped working as a teacher 12 years earlier after marrying a successful business executive and having the first of her two children. On interviewing, she spoke of a favorite aunt who had died of breast cancer after disfiguring surgeries, and of her own fear of a similar lesion. She was plagued by the thought that the loss of a breast would cause her husband to lose interest and abandon her. She had not informed her husband of her current medical situation. Meeting subsequently with both husband and wife, the psychiatrist gave explicit information about the possibility of malignancy and treatment options. The husband's manifest interest, support, and affection were reassuring; after the mammogram, a benign lump was removed. Discovery of the meaning to the patient of the illness and the procedure permitted an intervention that sufficiently reduced her anxiety to allow evaluation and treatment. As with any situational anxiety, the fear of serious or fatal illness can be managed with education, support, cognitive and behavioral strategies, and at times, the short-term use of benzodiazepines. Review of a patient's conceptualization of his or her medical condition, the procedures the patient faces, and the patient's interpretation of symptoms offers the physician the opportunity to correct cognitive distortions that may needlessly engender anxiety. Care should be taken in discussing symptoms and procedures, with sensitivity to an individual's coping style. The clinician should elicit the patient's conceptualization of his or her condition (or upcoming procedure) and provide corrective information when distortions are encountered. Additional strategies may be helpful when phobias about select medical procedures are encountered. For example, the enclosed chamber of the magnetic resonance imaging (MRI) scanner presents a phobic challenge to some individuals, engendering fears of overwhelming anxiety because of the inability to “escape” the MRI scanner quickly. For individuals with a history of 392 claustrophobia, panic disorder, or PTSD, pre-treatment with medications (e.g., benzodiazepines) or CBT may be required. In less severe cases, anxiety may be managed with simple procedures designed to maximize the patient's sense of safety and control. For example, compliance and comfort during the MRI scan may be aided by explaining to the patient the periods when he or she can shift positions or rub his or her hands together, the patient's ability to communicate with the nurse or technician, the patient's understanding of sounds and sensations to be experienced during the procedure, and the patient's ability to terminate the procedure, if need be. Initial practice of being moved into and out of the scanning chamber before the actual experience, as well as discussion of normal sensations of heat and anxiety experienced by patients while being scanned, can help normalize the experience and prevent catastrophic interpretations. There is evidence from analogue studies that information about the somatic sensations to be experienced during a procedure can help reduce anxiety and panic reactions.40 Instruction in comforting imagining may also aid the patient in tolerating the procedure. Anxiety that occurs in patients with a known and potentially fatal illness is more accurately termed fear because there is a known danger. Such fear, however, can adversely affect the course of illness and treatment. A study of survivors of MI, for example, indicated that 95% had increased tension and anxiety, and of one group of post-MI patients discharged from the hospital, 40% did not return to work; in 80%, psychological impairment, including anxiety, was the cause.41 Worry that activity will cause further heart damage or death interferes with rehabilitation and the return to autonomous function. The most effective therapeutic approaches for these patients center on education, group discussion, and support and stress management techniques.42 Anxious patients with a diagnosed serious or fatal illness require treatment that includes education in addition to the possible use of supportive, cognitive-behavioral, or insight-oriented psychotherapy and anxiolytic or antidepressant medications. Among patients with medical disorders, such as gastrointestinal (GI) disorders or allergies, the course and symptoms of the illness may be exacerbated by anxiety.42,43 Anxiety, as with other emotional responses, may adversely affect normal physiologic function; asthma symptoms are exacerbated by emotional arousal or stress, and the increased symptoms generate further anxiety.44 Psychological and emotional responses and behavior possibly affect the survival of patients with cancer through effects on the immune system.45 Medical Illnesses That Mimic Anxiety Disorder Anxiety symptoms may be the principal manifestation of an underlying medical illness.46 Of patients referred for psychiatric treatment, 5% to 42% have been reported as having an underlying medical illness responsible for their distress, with depression and anxiety as frequent complaints.47,48 Of reported cases of medical illnesses causing anxiety symptoms, 25% have been secondary 393 to neurologic problems; 25% to endocrinologic causes; 12% to circulatory, rheumatoid, or collagen vascular disorders and chronic infection; and 14% to miscellaneous other illnesses.46 A most common cause of anxiety may be alcohol and drug use; the anxiety results from either intoxication or, more typically, withdrawal states.49 The clinical presentation of anxiety in the medical setting takes many forms. The bewildering array and variable nature of the physical and psychic symptoms reported by anxious patients may lead the physician to overlook symptoms related to another disorder.4 The relative contribution of situational, psychiatric, and physiologic factors to the presentation of anxiety-like symptoms in a medical patient is often murky. The number of medical illnesses, furthermore, that may generate or exacerbate anxiety symptoms (Table 13-2) clearly renders an exhaustive evaluation for each of them impractical. A thorough yet efficient evaluation of the differential diagnostic possibilities, however, includes the following considerations:46,50 Table 13-2 Selected Medical Causes of Anxiety Endocrine Adrenal cortical hyperplasia (Cushing's disease) Adrenal cortical insufficiency (Addison's disease) Adrenal tumors Carcinoid syndrome Cushing's syndrome Diabetes mellitus Hyperparathyroidism Hyperthyroidism Hypoglycemia Hypothyroidism Insulinoma Menopause Ovarian dysfunction 394 Pancreatic carcinoma Pheochromocytoma Pituitary disorders Premenstrual syndrome Testicular deficiency Drug-Related Intoxication Analgesics Antibiotics Anticholinergics Anticonvulsants Antidepressants Antihistamines Antihypertensives Antiinflammatory agents Antiparkinsonian agents Aspirin Caffeine Chemotherapy agents Cocaine Digitalis Hallucinogens Neuroleptics Steroids Sympathomimetics 395 Thyroid supplements Tobacco Withdrawal Ethanol Narcotics Sedative–hypnotics Cardiovascular and Circulatory Anemia Cerebral anoxia Cerebral insufficiency Congestive heart failure Coronary insufficiency Dysrhythmias Hyperdynamic β-adrenergic state Hypovolemia Mitral valve prolapse Myocardial infarction Type A behavior Respiratory Asthma Hyperventilation Hypoxia Pneumonia Pneumothorax Pulmonary edema 396 Pulmonary embolus Immunologic-Collagen Vascular Anaphylaxis Polyarteritis nodosa Rheumatoid arthritis Systemic lupus erythematosus Temporal arteritis Metabolic Acidosis Acute intermittent porphyria Electrolyte abnormalities Hyperthermia Pernicious anemia Wilson's disease Neurologic Brain tumors (especially in the third ventricle) Cerebral syphilis Cerebrovascular disorders Combined systemic disease Encephalopathies (toxic, metabolic, infectious) Epilepsy (especially temporal lobe epilepsy) Essential tremor Huntington's disease Intracranial mass lesion Migraine headaches 397 Multiple sclerosis Myasthenia gravis Organic brain syndrome Pain Polyneuritis Post-concussive syndrome Post-encephalitic disorders Posterolateral sclerosis Vertigo (including Ménière's disease and other vestibular dysfunction) Gastrointestinal Colitis Esophageal dysmotility Peptic ulcer Infectious Disease Acquired immunodeficiency syndrome Atypical viral pneumonia Brucellosis Malaria Mononucleosis Tuberculosis Viral hepatitis Miscellaneous Nephritis Nutritional disorders Other malignancies (e.g., oat cell carcinoma) 398 1. In a patient with a known medical illness, the condition and its associated complications and treatment may be the cause of anxiety. For example, in the asthmatic patient, hypoxia, respiratory distress, and sympathomimetic bronchodilators may all contribute to the experience of anxiety. In some patients, risk factors or predisposition, such as a family history of medical illness capable of causing anxiety-like symptoms (e.g., thyroid disease), may be clues to diagnosis. 2. In medical illnesses considered mimics of anxiety, the quality of anxiety symptoms when closely examined may be different from that seen in primary anxiety disorders. For example, Starkman and associates51 studied 17 patients with pheochromocytoma and compared their anxiety symptoms with those of a group of 52 patients with anxiety and related disorders. Most patients with pheochromocytoma did not meet the criteria for panic disorder or generalized anxiety disorder (GAD); none developed agoraphobic symptoms, and their overall severity of symptoms was lower. There was a significant lack of psychological as opposed to physical symptoms of anxiety in most of these patients. 3. Similarly, patients with primary anxiety disorders are more likely to have emotional trauma related to the onset of anxiety, daily symptoms, neurotic features, and gradual resolution of symptoms after an attack and are less likely to have a loss of speech or consciousness during an episode of anxiety than are patients with anxiety associated with temporal lobe epilepsy.52 Thus, the lack of a significant emotional experience of anxiety or the occurrence of anxiety only coincidental with particular physical events (e.g., a run of ventricular tachycardia on a cardiac monitor or spike activity on an electroencephalogram) may suggest the presence of an organic anxiety syndrome. Evaluation directed toward the somatic system (e.g., GI or cardiac) most prominently affected by anxiety symptoms may provide the greatest yield from further diagnostic investigations. 4. In patients with an onset of anxiety symptoms after the age of 35 years, a lack of personal or family history of anxiety disorders, a negative childhood history of anxiety symptoms, an absence of significant life events heralding or exacerbating anxiety symptoms, a lack of avoidance behavior, and a poor response to standard anti-anxiety agents, the presence of an organically based anxiety syndrome should be considered. 5. Even for the apparently healthy patient, particular scrutiny should be directed at more common conditions associated with anxiety: arrhythmias, thyroid abnormalities, excessive caffeine intake, and other drug use. Anxietylike symptoms may be the first clue to a withdrawal syndrome in a patient with unreported regular sedative–hypnotic (e.g., ethchlorvynol, glutethimide, or a benzodiazepine) or alcohol use before admission to the hospital. Intoxication or withdrawal from prescription or over-the-counter medication or substances of abuse should also be suspected. Up to 3% of individuals have been reported to 399 develop psychiatric symptoms after using prescribed or over-the-counter medication.53 Case 4 A psychiatric consultation was requested from the medical service for Ms. D, a 31-year-old secretary, who developed anxiety attacks shortly after learning that she had contracted syphilis from her boyfriend. She had previously experienced spontaneous anxiety attacks in her mid-20s that had remitted early in a 6-month course of the TCA imipramine, and she had been symptom-free since. During the interview with the psychiatrist, Ms. D manifested anger and sadness about her boyfriend's infidelity and her own victimization, as well as anxiety about the future of their relationship. Her anxiety attacks, however, were different from those she had previously experienced. They consisted of blurred vision; dull bi-parietal headaches, primarily left-sided; numbness in her extremities; and feelings of dizziness. She reported feeling anxious after the onset of these symptoms. On further questioning, Ms. D described a history of menstrual irregularities over the past 2 to 3 years, and galactorrhea. Her prolactin level was found to be elevated, and a computed tomography scan revealed a pituitary adenoma. Surgical resection of the adenoma resulted in resolution of her anxiety attacks, although she elected to pursue psychotherapy to consider issues raised by the difficulties in her relationship. This case serves to illustrate the following points. The presence of a history of an anxiety disorder or a recent stressor does not eliminate the need to consider medical illness in the differential diagnosis of a new or different presentation of anxiety. Ms. D's experience of anxiety attacks was primarily somatic, and it was fortuitous that she had a history of more typical anxiety attacks for comparison; the nature of her symptoms led to a careful exploration for neurologic disease and allowed an appropriate and timely intervention. Anxiety That Mimics Medical Illness The autonomic arousal associated with anxiety states allows anxiety to present as a great imitator of medical illness. Patients with anxiety disorders repeatedly visit their primary care physicians or make the rounds of a variety of medical practitioners to seek a medical diagnosis to explain their symptoms. Along the way, they may be considered hypochondriacs, deceptive, or just nervous, and they may receive benzodiazepines or reassurance but fail to be offered adequate or definitive treatment. Patients with untreated panic disorder, for example, have increased rates of alcoholism and sedative–hypnotic abuse, presumably in an attempt to self-medicate.21,54 Sheehan and associates55 noted that 70% of patients with panic disorder in their series had been to at least 10 medical practitioners without receiving a diagnosis or adequate treatment. They had high somatization scores on the Symptom Checklist-90, which decreased with the treatment of the panic disorder. The majority of these patients met the 400 criteria for somatization disorder and tended to focus on the somatic symptoms of the untreated panic disorder. The nature of a patient's complaints may contribute to missed diagnosis and misdiagnosis. More than 90% of patients with panic present primarily with somatic complaints.21 Although 95% of patients with mood or anxiety disorders are correctly diagnosed if the affective symptoms are their presenting complaint, only 48% are accurately assessed if they present with somatic complaints.56 Individuals with somatization disorder are nearly 100 times more likely than those in the general population to suffer from a co-morbid panic disorder.57 Of 55 patients with panic disorder referred by primary care physicians in one study, 49 (89%) initially presented with one or two somatic complaints and were misdiagnosed for months to years.21 The three most common somatic loci of symptoms were cardiac, GI, and neurologic, with 45 (81%) of the 55 patients presenting with a pain complaint. These patients may focus on specific physical symptoms, such as chest pain or diarrhea, thereby obscuring other anxiety symptoms, or they may deny affective or cognitive responses to avoid the stigmatization of psychiatric illness. As noted, anxiety may also exacerbate pre-existing physical conditions, such as asthma, which then become the focus of the attention of both the patient and the physician. The cost of unrecognized and untreated anxiety disorders in patients is high in terms of continued suffering, inefficient use of medical personnel, and costly repetitive diagnostic procedures. In one study of “high utilizers” of medical services, 58% had a mood or anxiety disorder, including 22% with panic disorder.58 Clancy and Noyes59 have documented the high rate of medical specialty consultations and procedures (most commonly cardiologic, neurologic, and GI) requested by patients with panic disorder. In one series of patients with chest pain who were undergoing coronary arteriography, Bass and co-workers60 noted that 61% of the patients with insignificant coronary disease had psychiatric morbidity on a standardized interview, as opposed to only 23% of those with significant coronary disease. In those with normal coronary arteries, the most common psychiatric diagnosis was an anxiety disorder. Recognition and treatment of the anxiety disorder, in some cases, may have eliminated the necessity for arteriograms. In another study, 30% of patients admitted to a cardiac care unit were determined to have no coronary disease but were subsequently diagnosed with panic disorder.61 Wulsin and colleagues62 noted that 43% of patients who presented to the Emergency Department (ED) with chest pain had panic attacks, and 16% had panic disorder; patients with panic disorder who presented to the ED with chest pain made more subsequent medical and ED visits than those without panic disorder.63 Richter and associates64 estimated that the average patient with noncardiac chest pain spends US$3500 per year on ED, physician, hospital visits, and medications. In one series,22 panic disorder exacerbated the symptoms of patients with pre-existing medical disease and led to multiple hospitalizations —a trend that was reversed with treatment of the panic disorder. Dirks and associates65 reported that patients with chronic asthma and high levels of anxiety had more hospitalizations than asthmatic patients with physiologic 401 illness of comparable severity but normal degrees of anxiety. Anxiety may play an especially important role in the intensification of hypochondriacal concerns. Once a fear of disease is activated, that fear provides a context for organizing subsequent experiences, including the experience of anxiety symptoms. The fear of disease helps direct attention to somatic symptoms, including anxiety-related symptoms, and can help engender a selfperpetuating cycle of vigilance, worry, and disease concern.66,67 Although consideration of the medical differential diagnosis for anxiety is crucial, recognition and treatment of anxiety disorders is essential in preventing inefficient use of medical resources and patient exposure to costly and occasionally dangerous diagnostic and therapeutic procedures. Failure to make the pertinent psychiatric diagnosis may result in a patient continuing to “doctor shop” in the search to discover “what's really wrong with me,” with repeated diagnostic procedures resonating with the patient's hypochondriacal concerns. Untreated anxiety can exacerbate symptoms of existing medical pathologic conditions and drive a cycle of escalating help-seeking behavior and hospitalization. Case 5 An ED psychiatric consultation was requested for Mr. E, a 35-year-old man, seen acutely by cardiology staff six times in the past month for chest pain and tachycardia. He had been admitted to the cardiac care unit twice, where MIs were ruled out. An extensive negative work-up at another hospital had included a cardiac angiogram. After being told “there's nothing wrong with your heart, you're just nervous” and being given a prescription for diazepam, he sought emergency treatment at our institution in the hope that “they'll find out what's wrong.” He had refused previous consultations with psychiatry in the fear that he would be dismissed as “a head case,” but he finally agreed to evaluation at the insistence of the medical team. He was an athletic-looking salesman in his 30s, a self-described “take-charge kind of guy” without any previous psychiatric or medical history. He had a family history of hypertension and was concerned about potential “inherited heart problems.” His electrocardiogram recorded a sinus tachycardia of 120 beats/minute and ST-T wave changes deemed secondary to the elevated rate. The episodic periods of anxiety, chest pain, tachycardia, diaphoresis, and hyperventilation had begun approximately a year earlier without clear precipitants during highway driving and had caused him to pull off the road and to seek emergency medical treatment. He reported anticipating long trips with trepidation lest the episodes of chest pain be repeated. His diagnosis was panic disorder with mild agoraphobia, and treatment was initiated with alprazolam. He felt reassured that he was not crazy and had a definable condition for which treatment was available. The panic attacks remitted shortly thereafter, as did the patient's use of emergency medical services. 402 Treatment with a number of agents can dramatically relieve the spells and secondary complications of panic disorders, thus underscoring the importance of early diagnosis. Furthermore, because of the physical nature of the symptoms, general medical and ED evaluators need to be alert to the clinical phenomena of a panic attack. Patients who describe their symptoms as anxiety or who evolve a major depression may be more likely to be identified as having a psychiatric disorder. Given the dramatic physical complaints in a variety of bodily systems, however, as with depression, in which somatic symptoms may dominate the presentation and mask diagnosis, an analogy may be made with missed or masked panic disorder. The absent report of the affective, behavioral, or cognitive components of a panic attack can obscure the diagnosis in the face of paroxysmal physical symptoms. One case report68 described a patient with a symptom picture that suggested a panic attack but the patient failed to describe the emotional experience of anxiety or panic; alexithymia, or the inability to describe one's emotions, was offered as a possible mechanism for the clinical picture. The predominance of physical symptoms or the absence of cognitive or behavioral responses, however, may not reflect alexithymia or a cognitive impairment, but rather variability in symptom expression. Some patients suffer panic attacks without experiencing a need to flee; others experience panic attacks without a sense of terror or dread, but do not necessarily lack the ability to describe their own emotions. Most patients with clinically significant panic attacks also suffer limitedsymptom attacks that feature only one or two physical symptoms. These may be interspersed with major attacks and may be either situational or unexpected, consisting, for example, of runs of tachycardia or bouts of flushing, hyperventilation, or dizziness. Panic disorder, in its early stages, may be manifested exclusively by such minor attacks. Similarly, as anti-panic therapy is effective, both unexpected and situational limited-symptom attacks may be the last vestige of the disorder or continue to represent a residual disorder. As stated, patients vary in the primary somatic locus of anxiety distress.50 For example, predominant panic attack symptoms may appear as cardiovascular symptoms (tachycardia or palpitations), neurologic symptoms (dizziness or paresthesias), respiratory symptoms (dyspnea), GI symptoms (diarrhea), and so forth. Recurrent limited-symptom attacks may therefore be initially indistinguishable from symptoms of a number of disorders in these systems (see Table 13-2). Limited-symptom attacks also may be a harbinger of progression to the full syndrome, but in some cases they may also be disabling themselves and progress to such panic disorder complications as persistent anxiety, phobic avoidance, and depression. Case 6 Mr. F, a 32-year-old married factory supervisor, had been out of work for 2 years because of stomach pain, nausea, and vomiting. He described his discomfort as “gnawing pains” that would occur paroxysmally, followed by 403 vomiting with little warning. In the previous 5 years, he had had extensive GI work-ups and medical management, vagotomy and pyloroplasty, and ultimately hemigastrectomy without relief of symptoms. He was totally disabled and was referred for psychiatric evaluation. The following features were noted: (1) His severe pain was paroxysmal with lower-grade persistent symptoms; (2) diazepam helped diminish, but did not eradicate, his symptoms; (3) he was homebound and described attacks of stomach pain and vomiting only when he left his apartment, e.g., to go shopping; (4) the onset had followed the break-up of a relationship; (5) a major depression had evolved. On treatment with sertraline (co-administered with diazepam), he experienced complete symptomatic relief in 6 weeks and with maintenance treatment, remained symptom free for 5 years. He sought and found a new job after treatment and has been continuously employed for the past 5 years. He recalled frequently needing to leave school as a child because of a nervous stomach. This case reflects a missed or masked diagnosis of panic disorder because of the predominance of a limited-symptom attack resembling a GI syndrome. Clues to a diagnosis of panic disorder were evident, and appropriate treatment led to dramatic improvement in this disabled patient. Features reminiscent of more typical patients with panic disorder were identified before definitive treatment, including severe paroxysmal and lower-grade persistent symptoms, onset with a major life event, agoraphobic features, a childhood history suggesting separation anxiety, partial relief with benzodiazepines, and secondary depression. No family history of panic attacks or agoraphobia was reported in this case. Panic Disorder Associated With Medical Illness An association between panic disorder and other medical illnesses has been described. More than one-third of patients with chronic obstructive pulmonary disease have an anxiety disorder, including 8% to 25% with panic disorder.69–71 Pollack and associates72 found an elevated prevalence of panic disorder (11%) among patients referred to a general hospital for pulmonary function testing, including two-thirds of those with chronic obstructive pulmonary disease. Almost half of all patients evaluated reported substantial symptoms of anxiety. Katon21 and Noyes and co-workers73 reported an increased incidence of peptic ulcers and hypertension in patients with panic disorder. Close to a third of patients with irritable bowel syndrome have panic disorder, and 44% of panic patients have irritable bowel syndrome; symptoms of both conditions improve with treatment of the panic disorder.74 Retrospective studies by Coryell and colleagues75 suggest an increased risk of premature mortality from cardiac disease in men with panic disorder. Patients with mitral valve prolapse (MVP) have been diagnosed much more frequently (30% to 50%) with panic disorder.76,77 Studies have indicated that the relationship is coincidental and there are no associations between MVP, panic 404 disorder, social anxiety disorder, or other anxiety disorders.78 405 Primary Anxiety Disorders Patients with a number of primary psychiatric disorders may present with anxiety in the medical setting. A history of psychiatric illness may precede the patient's entry into the medical setting and then be exacerbated by the medical condition. For some, however, the onset of symptoms associated with a psychiatric disorder is provoked by the stress of medical illness. Panic Disorder A panic attack usually lasts minutes with fairly stereotypical physical, cognitive, and behavioral components. Patients with panic disorder may experience these attacks intermittently over time or in clusters and, as stated, may develop a number of complications, including persistent anxiety, phobic avoidance, depression, alcoholism, or other drug overuse. Physical symptoms (e.g., cardiac, respiratory, neurologic, and GI symptoms) are experienced as if there is a sudden surge of autonomic, primarily sympathetic, arousal. Cognitively, the patient feels a sense of terror or fear of losing control, dying, or going crazy and behaviorally often feels driven to flee from the setting in which the attack is experienced to a safe, secure, or familiar place or person. The initial attack that appears to “turn on” the disorder, the herald attack, is particularly well remembered by the patient. Subsequent attacks may be a mixture of spontaneous, unexpected attacks and those preceded by a buildup of anticipatory anxiety; the latter, called situational attacks, occur in settings in which the patient might sense being at risk for panic, such as crowded places. Attacks may be major, with four or more symptoms, or limited-symptom attacks with fewer symptoms. Panic disorder has its typical onset in early adult life and afflicts women two to three times as commonly as men. More than half of patients with panic disorder have a history of anxiety disorders beginning in childhood.79 The disorder is familial and very likely has a genetic basis, given a higher concordance in monozygotic as compared with dizygotic twins,80 but it is not clear whether a genetic influence is specific to panic disorder or whether it represents a general anxiety-proneness that may be expressed variably as any of a number of anxiety disorders. The onset of the disorder in a clinical population typically follows either a major life event, such as a loss, threat of loss, other upheavals in work or home situations, or some physiologic event, such as medical illness (e.g., hyperthyroidism, vertigo) or drug use (marijuana, cocaine). For example, some patients whose first or herald attack appears to be triggered by a physiologic perturbation, such as following marijuana use, may continue thereafter with persistent or recurrent symptoms without further drug use. A panic attack, like an endogenous false alarm, appears to turn on a state of vigilance or post-panic anxiety that resembles GAD. Between attacks, patients 406 may remain symptomatic with low-level constant anxiousness and anticipatory anxiety that may crescendo into panic in certain situations or be punctuated by panic unexpectedly. In this state of vigilance, phobic avoidance may occur as a complication. The patient may develop mild or extensive phobic avoidance, usually of travel or places of restricted escape, immediately after the onset of attacks, after a number of attacks, or never at all. In some cases, the phobic avoidance evolves as a progressive constriction with the cumulative avoidance of settings where attacks have occurred. Major depressive episodes may also complicate the course of the patient with panic disorder and occur in up to two-thirds of cases.81 For some, the demoralization attending the sustained distress and progressive disability of panic disorder extends to a typical depression with characteristic signs and symptoms. As noted, the relationship between panic and depression is a complicated one, however. Some patients manifest no depressive symptoms; for others, it is unclear which disorder is primary because symptoms arise concurrently. Alcohol use can temporarily tame the distress of panic disorder but soon yields to rebound symptoms, thereby setting the stage for alcohol overuse. Generalized Anxiety Disorder Patients with GAD suffer from chronic worry about a number of life circumstances (e.g., finances or danger to loved ones) that is difficult to control and is present on more days than not, for longer than 6 months.2 These patients are often called “nervous” or “worriers” by family or friends. Their anxiety is accompanied by a number of somatic and cognitive symptoms associated with motor tension and autonomic hyperactivity (e.g., muscle tension, restlessness, difficulties concentrating, and sleep disturbances). Although the disorder may be differentiated from panic disorder by the persistent rather than episodic nature of the symptoms, careful questioning often reveals that patients with GAD may experience panic attacks as well.82,83 Many patients with GAD in the medical setting manifest anxiety in addition to the symptoms of other psychiatric disorders (e.g., panic disorder, depression, or alcohol abuse).84 Specific Phobias Patients with specific phobias are afraid of circumscribed situations or objects (e.g., heights, closed spaces, animals, or the sight of blood).2 Exposure to the feared stimulus results in intense anxiety and avoidance that interferes with the patient's life. Some patients are so afraid of needles or blood, that compliance with procedures in the medical setting is nearly impossible. Acute treatment with benzodiazepines may decrease the patient's anxiety to the point where he or she agrees to treatment. The only consistently effective treatment for specific phobias, however, is behavioral therapy, a technique that involves exposure and desensitization to the feared object or situation.85 407 Social Phobia (Social Anxiety Disorder) Social phobia, also referred to as social anxiety disorder, is diagnosed when the patient perceives that he or she will be the object of public scrutiny and fears that he or she will behave in a way that will be humiliating or embarrassing.2 This perception leads to persistent fear and avoidance, or to endurance with intense distress. Circumscribed situations may be feared (e.g., speaking before a group, performance anxiety, writing or eating in the presence of others, or urinating in public lavatories); many patients experience more global difficulties in which most social interactions are difficult. Again, depression and alcoholism can frequently occur with social phobia.86,87 Patients with a social phobia may have intense anxiety in the hospital because they are under intense scrutiny by others. Long-term treatments include antidepressants with selective serotonin re-uptake inhibitors (SSRIs) (fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram), serotonin–norepinephrine re-uptake inhibitors (SNRIs) (venlafaxine), and monoamine oxidase inhibitors (MAOIs) (phenelzine, tranylcypromine) generally being more effective than TCAs (e.g., imipramine, desipramine, nortriptyline), β-blockers (for performance anxiety rather than generalized social phobia), or CBT. Some reports support the clinical efficacy of high-potency benzodiazepines (HPBs) (e.g., clonazepam,88 alprazolam89) for the treatment of social phobia; when immediate intervention is necessary, the use of these agents is appropriate. Post-traumatic Stress Disorder Patients with PTSD have experienced or witnessed a traumatic event involving death or serious injury to themselves or others and responded with feelings of intense fear, horror, or helplessness.2 Afflicted patients frequently re-experience the traumatic event. They have recurrent dreams or suddenly act or feel as though the event is recurring (i.e., a flashback). Individuals with PTSD frequently avoid situations that remind them of the event and may become numb, irritable, or hypervigilant and experience difficulty with sleep or concentration. Although much attention has been directed toward PTSD in combat veterans, PTSD can occur in civilians who suffer life-threatening accidents or assaults or who have survived natural disasters. PTSD is unfortunately common and often unrecognized in the medical setting, with reported rates of PTSD in over one-third of patients hospitalized after traumatic injury, such as occurring in motor vehicle accidents, assaults, or fires.31,90 Injured patients who develop PTSD have increased functional impairment and problem-drinking when followed up a year after surgery.91 Acute stress disorder involves the development of dissociation and reexperiencing symptoms along with avoidance, anxiety, increased arousal, and significant distress or impairment lasting up to 4 weeks after a trauma.2 The presence of acute stress disorder is associated with the development of PTSD.92 There is growing interest in whether early intervention for trauma victims can prevent the development of PTSD. There are scarce data on the 408 effectiveness of primary PTSD prevention.93 Despite being a widely used intervention after trauma, data show that single-session debriefing after a traumatic event has no benefit in preventing PTSD.93,94 In contrast, more extensive, multiple-session cognitive-behavioral interventions incorporating information, cognitive re-structuring, and exposure elements, appear effective.93,95 Pharmacologic interventions have also demonstrated potential benefit in reducing the morbid sequelae of trauma. Glucocorticoid administration is currently the most effective pharmacologic intervention in preventing PTSD.93,95 Studies consistently show a reduced incidence of PTSD after administration of high doses of hydrocortisone after different types of traumatic events in both critically ill as well as healthy cohorts. SSRIs are considered first-line for the treatment of chronic PTSD,96 however early use aimed at preventing PTSD15 is equivocal, with one small RCT showing no benefits versus placebo with escitalopram and another small RCT demonstrating lower PTSD rates with sertraline versus placebo.93 It should be noted that the study samples were small, the ages of participants varied greatly, as did the nature of traumatic events in each study. Propranolol has been investigated in numerous studies as a PTSD prevention strategy. While there have been mixed results, the majority of studies including large RCTs have not shown that propranolol is effective in PTSD prevention.93 Benzodiazepines have been consistently shown to have no effect on preventing PTSD when given after a traumatic experience.93 Furthermore, they may have “PTSD-enhancing” effects by interfering with extinction learning.95 Morphine has been shown to be associated with lower rates of developing PTSD when given after traumatic events, however, these have been small observational studies and no RCTs are currently available to confirm its benefits.93,95 Ketamine, a dissociative NMDAreceptor antagonist, has been studied as a potential strategy to prevent PTSD in surgical patients with mixed results; further study is warranted.93 Though early treatment strategies aimed at preventing PTSD are scarce and understudied, it is well established that both CBT97 and SSRI pharmacotherapy are effective first-line interventions for the treatment of established or chronic PTSD.98 They are frequently co-administered to improve outcome. Obsessive–Compulsive Disorder Patients with OCD suffer from recurrent, intrusive, unwanted thoughts (i.e., obsessions, such as the fear of hurting a loved one or the fear of contamination) or compulsive behaviors or rituals (such as repetitive hand-washing or checking a door multiple times to make sure it is locked).2 The obsessions and compulsions are distressing and time consuming (i.e., they may take more than 1 hour/day) and interfere with the patient's normal function. In the medical setting, the patient with OCD may suffer a marked increase in anxiety if physical disability or hospital routine makes it impossible for him or her to perform compulsive rituals. CBT aimed at reducing the patient's obsessive thoughts and compulsive behavior has demonstrated clear efficacy for OCD. Benzodiazepine therapy may be necessary to control overwhelming anxiety, 409 particularly in acute treatment. Effective long-term treatments include use of serotonergic antidepressants (e.g., SSRIs, clomipramine) as well as behavioral therapy. Other Psychiatric Disorders Anxiety symptoms may be associated with a number of psychiatric disorders (such as schizophrenia, depression, and bipolar disorder) other than primary anxiety disorders. Vague uneasiness extending to severe anxiety may either precede or accompany the symptoms of schizophrenia. Patients with significant degrees of anxiety may have a reduced level of function and manifest withdrawal that superficially resembles schizophrenia. The presence of hallucinations, delusions, and bizarre and disordered thinking, a marked degree of social withdrawal, and a characteristic pre-morbid personal and family history usually allows an uncomplicated differentiation of schizophrenia from anxiety disorders. The relationship between anxiety and depression is complex. Weissman and co-workers99 reported an increased prevalence of both panic disorder and depression in the families of probands with both disorders. One estimate holds that one-third of patients with panic disorder, with or without agoraphobia, develop a secondary major depression, and 22% have had a major depressive disorder before developing panic disorder.100 The incidence of a major depressive episode in patients with panic disorder has been reported as ranging between 28% and 90%, depending on the diagnostic criteria used.101 Leckman and associates102 found that 58% of a group of depressed patients had anxiety symptoms meeting criteria for agoraphobia, panic disorder, or GAD. Although this overlap between syndromes can make the distinction between anxiety and depression difficult, a number of clinical considerations may be useful. Psychomotor retardation, persistent dysphoria, early morning awakening, diurnal variation, a sense of hopelessness, and suicidal thoughts are more indicative of depression. Patients with an anxiety disorder have often not lost interest in their usual activities but rather have lost the ability to negotiate them comfortably. They are more likely to report autonomic hyperactivity, derealization, perceptual distortions, and anxious impatience than hopelessness.49 Advances in neurobiology at this time offer few diagnostic markers for differentiating anxiety and depressive disorders. The sleep of patients with panic disorders differs from the sleep of depressives during allnight polysomnograms.103 There are also differences in physiologic parameters and platelet receptor-binding patterns between anxious and depressed patients.104,105 The principal concern in differentiating depression from anxiety is to not overlook treatment with an antidepressant and, in particular, to avoid the common scenario of prescribing only a benzodiazepine for the anxiety component of a depression, thereby leaving the depression untreated. Fortunately, the frequent overlap in clinical presentations between primary depressive and primary anxiety disorders is mirrored by an overlap in 410 therapeutic considerations. One important consideration, however, is the possibility that depressed symptoms may reflect an underlying bipolar (manicdepressive) disorder. Anxiety disorders are a common co-morbidity among bipolar individuals.106 However, the use of antidepressants in bipolar patients may precipitate mania and provoke greater mood cycling. Bipolar disorder should be considered in the differential diagnosis of depression, particularly in those patients with a history of marked mood instability or a family history of manic-depressive illness, as well as in individuals who become more agitated or dysphoric after antidepressant administration. For bipolar patients, use of an anticonvulsant may treat both the mood and the anxiety disorder, with use of benzodiazepines, in preference to antidepressants, considered for persistent anxiety in individuals without a substance abuse diathesis. Although cognitivebehavioral interventions for anxiety and depression differ in both their focus and procedures, it is not unusual for treatment of one condition to extend benefit to the associated disorder. For example, the CBT of panic disorder is associated with improvement in co-morbid depression. Nonetheless, comorbidity generally serves as a predictor of worse overall treatment response to CBT, just as it does for pharmacologic approaches.107 411 Treatment The nature of the medical setting favors expedient interventions, such as drug treatment to ease acute distress, because of the time-limited nature of medical and surgical stays (Table 13-3). Nonetheless, as illustrated by the case examples, comprehensive assessments, including systematic scrutiny of cognitive and psychosocial factors, may lead to practical interventions short of formal psychotherapy, including CBT. In addition, disrupted relations with family members may be provocative, and family interventions may prove therapeutically expedient. TABLE 13-3 Selected Pharmacologic Treatments for Anxiety Disorders AGENT USUAL INITIAL DOSAGE (mg) DOSAGE RANGE (mg) CHIEF DOSAGE LIMITATIONS DISORDERS Tricyclic Antidepressants (TCAs) Imipramine 10–25 150–300 Jitteriness, TCA side effects PD, AG, GAD, PTSD, OCD Clomipramine 25 25–250 Sedation, weight gain, TCA side effects PD, AG, GAD, PTSD Monoamine Oxidase Inhibitors (MAOIs) Phenelzine 15–30 45–90 Diet, MAOI side effects PD, AG, SP, ?GAD, OCD, PTSD Selective Serotonin Re-Uptake Inhibitors (SSRIs) Fluoxetine 10 10–80 SSRI side effects PD, AG, SP, OCD, PTSD Sertraline 25 25–200 SSRI side effects PD, AG, SP, OCD, PTSD Paroxetine 10 10–50 SSRI side effects PD, AG, SP, OCD, PTSD Paroxetine-CR 12.5 12.5–62.5 SSRI side effects PD, AG, SP, OCD, PTSD Fluvoxamine 50 50–300 SSRI side effects PD, AG, SP OCD, PTSD Citalopram 10 20–60 SSRI side effects PD, AG, SP, OCD, PTSD Escitalopram 5 10–20 SSRI side effects PD, AG, SP, OCD, PTSD Serotonin–Norepinephrine Re-Uptake Inhibitor (SNRI) Venlafaxine 37.5 75–225 SSRI side effects, hypertension PD, AG, SP, OCD, PTSD Benzodiazepines Alprazolam 0.25 QID 2–10/day Sedation, discontinuation syndrome PD, AG, GAD, SP, ?SpP Clonazepam 0.25 QHS 1–5/day Abuse, psychomotor and memory impairment PD, AG, GAD, SP, ?SpP Diazepam 2.5 5–30/day – GAD, SpP, PD, SP Other Anxiolytics Buspirone 5 TID 15–60/day Dysphoria GAD Propranolol 10–20 10–160/day (maintenance use) Depression SP, ?PD, ?GAD AG, agoraphobia; GAD, generalized anxiety disorder; OCD, obsessive–compulsive disorder; PD, panic disorder; PTSD, post-traumatic stress disorder; SP, social phobia; SpP, specific phobia. Pharmacologic Treatment of Panic Disorder The drug treatment of anxiety essentially involves selecting agents for panic, GAD, or both. As with recognizing the primacy of depression in some anxious patients, if the presence of panic attacks is overlooked, treatment for generalized anxiety alone is likely to be inadequate, and patient suffering will continue. Familiarity with panic disorder, its complications, and its treatments is a necessary resource in evaluating and caring for anxious patients. Although early intervention offers the likelihood of preventing complications, many patients come for treatment after years of symptoms and disability. Even in the face of chronicity, however, most patients achieve substantial if not dramatic benefit with available treatments, which include anti- 412 panic pharmacotherapy and CBT. Given the apparent primacy of the panic attack in the distress and evolution of complications of the disorder, our usual approach is to initiate anti-panic medications for patients who continue to experience panic attacks, with the expectation of regression and remission of complications once the attacks have ceased. For patients with residual phobic avoidance despite the prevention of panic attacks, behavioral and cognitive strategies are employed. For some patients, behavioral and cognitive strategies are employed initially, especially when the frequency and intensity of unexpected panic are minimal, with pharmacotherapy subsequently applied if emergence or exacerbation of panic attends the behavioral program. Antidepressants The SSRIs (including fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine) have become first-line agents for the treatment of panic disorder as well as other anxiety disorders108,109 because of their broad spectrum of efficacy, favorable side effect profile, and lack of cardiotoxicity. Although effective, these agents may worsen anxiety for some patients at the initiation of treatment. Thus, treatment of panic patients or the anxious depressed should be initiated at half or less of the usual starting dosage (e.g., fluoxetine 5–10 mg/day, sertraline 25 mg/day, paroxetine 10 mg/day––or 12.5 mg/day of the controlled-release formulation––citalopram 10 mg/day, escitalopram 5 mg/day, and fluvoxamine 50 mg/day) to minimize the early anxiogenic effect. Dosages can usually be raised, after about 1 week of acclimation, to typical therapeutic levels. Typical target dosages for this indication are fluoxetine 20–40 mg/day, paroxetine 20–60 mg/day (25–72.5 mg/day of the controlled-release formulation), sertraline 100–150 mg/day, citalopram 20–60 mg/day, escitalopram 10–20 mg/day, and fluvoxamine 150– 250 mg/day, although some patients may respond at lower levels. Patients with OCD and PTSD may require higher dosages (e.g., fluoxetine 60–80 mg/day) to receive maximal benefit. Onset of benefit with the SSRIs and other antidepressants usually occurs after 2 to 3 weeks of treatment. Although generally better tolerated for acute and long-term treatment than older available classes of antidepressants, SSRIs may be associated with transient or persistent adverse effects, including nausea and other GI symptoms, headaches, sexual dysfunction, and apathy. Despite their reputation as stimulating agents, sleep disturbance is generally not a persistent or significant problem during SSRI therapy. The SSRIs are usually administered in the morning; emergent sleep disruption can usually be managed by the addition of hypnotic agents. The extended-release SNRI venlafaxine has also demonstrated efficacy for the treatment of panic disorder and the other anxiety disorders. As with other antidepressants, it may cause uncomfortable stimulation early in the treatment of anxious patients, so dosing should be initiated with low dosages (i.e., venlafaxine 37.5 mg/day). Other antidepressants, such as mirtazapine, are also probably effective for the treatment of anxiety disorders, but the systematic data supporting their use for these indications are limited. Trazodone appears 413 to be less effective for panic disorder than other agents; studies assessing the effectiveness of bupropion for panic disorder are small and have shown mixed results. The TCA imipramine hydrochloride has well-established efficacy in panic disorder.110 Although other TCAs are probably also effective (e.g., desipramine is frequently employed because of its lower anticholinergic burden), this class of agents has several drawbacks, including a delayed onset of benefit and treatment-emergent adverse effects. In addition to the usual TCA side effects (such as dry mouth, constipation, and orthostatic hypotension), panic patients are particularly prone to a sudden worsening of their disorder with the first doses. To minimize the effect of this adverse response, treatment can be initiated with small test doses (e.g., 10 mg of imipramine hydrochloride). If this is well tolerated, standard antidepressant dosing can be pursued; for others, the adverse response typically fades over a few days, thus allowing an upward titration of dosage. For a small percentage of patients, this apparent worsening of the disorder does not subside. Mavissakalian and Perel111 reported that a reasonable target dosage of imipramine for treatment of panic disorder and agoraphobia in most patients is approximately 2.25 mg/kg per day (usually between 100 and 200 mg/day for most patients), with a total plasma level of 75 to 150 ng/mL for imipramine and its metabolite, desipramine. The MAOI phenelzine has stood up well in clinical use and controlled trials,110 and many clinicians believe that MAOIs may be the most comprehensively effective agents for treating panic disorder, blocking panic attacks, relieving depression, and offering a confidence-enhancing effect of considerable value to the patient needing to recover from vigilance and phobic avoidance. Except for postural hypotension, MAOIs are free of most of the early TCA and SSRI side effects, including the anxiogenic response. Unfortunately, as treatment proceeds, a variety of challenging problems emerge, including insomnia, weight gain, edema, sexual dysfunction, nocturnal myoclonus, and other unusual symptoms. Further, many anxious patients are most circumspect about the dietary precautions and instructions about hypertensive crises. Because the SSRIs and the MAOIs offer similar spectra of efficacy in terms of treating panic disorder, social phobia, and atypical depressive symptoms, along with a superior safety and side-effect profile, they are generally used first in most patients. MAOIs, however, may be effective in patients failing to respond to other interventions; thus, although this has not been systematically studied, many clinicians believe that no patient should be considered truly treatment refractory to pharmacotherapy until the patient has had an MAOI trial. Benzodiazepines When treatment refusal, treatment discomfort from side effects, and treatment failure are considered, the need for a better-tolerated and effective anti-panic treatment is apparent. In some respects, benzodiazepines, such as alprazolam and clonazepam, fit this need. They have demonstrated anti-panic efficacy as well as patient acceptability and a reasonable record of safety. In addition, they provide the speed of action that is desirable in a medical setting. Although it 414 was once believed that higher-potency agents, such as alprazolam and clonazepam, were more effective than lower-potency agents, such as diazepam, for the treatment of panic, it appears that all benzodiazepines may be effective at equivalent dosages (i.e., 4 mg/day of alprazolam and 40 mg/day of diazepam).112 The usual dosage range for most panic disorder patients receiving alprazolam is 2 to 8 mg/day, with most achieving a benefit from around 4 to 6 mg/day. Clinical response is evident early, but lower dosages are necessary to initiate treatment so that the patient can accommodate to sedation. Most patients adapt within a few days to the sedating effects, and this allows a stepwise increase in panic-blocking doses. Adaptation to sedation usually occurs without a loss of therapeutic benefit, but some upward adjustment may be required after the first 2 weeks. A small percentage of patients appear particularly sensitive to the drug and experience persisting sedation despite time and careful titration. Alprazolam must be given in divided doses, usually three to four times a day, because of its relatively short duration of action; a recently introduced extended-release formulation permits once-a-day dosing. It does not change the elimination half-life or need for a gradual taper with discontinuation. Despite the ease of administration of alprazolam and frequently dramatic results even in the first days of treatment, clinical drawbacks include concerns about abuse and dependency, rebound symptoms between doses, withdrawal, and early relapse. The abuse potential of alprazolam, like that of other benzodiazepines, varies widely among clinical populations; patients with a history of alcohol or other substance abuse are most at risk for abusing benzodiazepines. Numerous studies are reassuring that panic patients treated with benzodiazepines do not experience therapeutic tolerance or dosage escalation; in fact, dosages of benzodiazepines generally decrease over the maintenance period, often despite the presence or persistence of untreated anxiety symptoms.113 Most well-informed panic and phobic patients who have endured severe distress over time treat their medication with respect and understand the wisdom of maintaining the lowest effective dose; thus, unless there is evidence that a particular patient is at risk, the use of this agent appears generally safe for the disorder under consideration. As with any benzodiazepine, without controlled prescribing for targeted symptoms, inappropriate use may occur. As seen with a benzodiazepine with a relatively short half-life, the discontinuation of alprazolam therapy, especially after longterm treatment, without a gradual taper tailored to the individual patient's sensitivity to decreasing dosages, may be followed by rebound symptoms (worsened anxiety) or a withdrawal syndrome. With the pharmacokinetic drawbacks associated with a short half-life agent in mind, the longer-acting high-potency benzodiazepine (HPB) clonazepam, has been effective for those patients who require an HPB. Because of its long halflife (15 to 50 hours), clonazepam is generally administered on a twice-a-day dosage schedule, with patients less likely to experience interdose rebound and withdrawal symptoms than on shorter-acting agents. 415 With a milligram-for-milligram potency approximately twice that of alprazolam, clonazepam's effective dosage range for panic patients is between 1 and 5 mg/day when given in morning and bedtime doses. Sedation is the limiting factor in dosage titration and is managed by initiating treatment with a low bedtime dosage and titrating upward if symptoms persist and sedation resolves. An initial dosage as low as 0.25 mg may be used in drug-naive patients or those particularly sensitive to benzodiazepines. Greater dosages may be given at bedtime than in the morning if the patient is not readily accommodating to sedation, but many patients function without sedation on equal morning and bedtime dosages, as with alprazolam. The effect of a daily dose on panic attacks and generalized anxiety is apparent within a few days. Some patients, for unclear reasons, develop depressive symptoms as a treatment-emergent adverse effect when taking alprazolam or clonazepam. Resolution of depressive symptoms typically occurs with the introduction of an antidepressant; benzodiazepine treatment can then be withheld with the expectation of a comprehensive response to the antidepressant. Combined treatment can again be used if anxiety symptoms break through the antidepressant treatment. Some clinicians initiate combined treatment with an antidepressant and an HPB to obtain the rapid anxiolysis associated with HPB treatment, decrease the activation associated with initiation of antidepressant therapy, and provide antidepressant coverage of co-morbid or benzodiazepine-induced depression. For many patients, the HPB can be tapered after a few weeks when the antidepressant begins to exert therapeutic effects; however, some patients remain on combined treatment with benefit and without adverse consequences. Pharmacologic Treatment of Generalized Anxiety As noted previously, the SSRIs and the SNRIs have become first-line pharmacologic agents for the treatment of anxiety disorders, including GAD. They are better tolerated than the older classes of antidepressants and have a broad spectrum of efficacy, which is a critical clinical concern given the high rates of co-morbidity, particularly depression affecting the generally anxious individual. In addition, SSRIs and SNRIs do not have significant abuse potential, which is an important consideration for generally anxious individuals with a predisposition to substance abuse. However, use of these agents may be associated with side effects, including sexual dysfunction and GI distress, that may adversely affect compliance. The delay in the onset of therapeutic benefit is a relative disadvantage for antidepressants as well as for buspirone; the call to intervene with medication for the anxious patient in the hospital typically requires a response with a more immediate-acting agent. Thus, benzodiazepines are usually used for acute management of anxiety, with antidepressant addition or substitution considered in patients requiring maintenance pharmacotherapy, particularly those with a depressive or substance abuse diathesis. Benzodiazepines, by dint of their efficacy, tolerability, and rapid onset of 416 effect, have long been the mainstay of anxiolytic pharmacotherapy, although the clinical decision to prescribe these agents for symptom relief is a difficult one. The attitudes of individual physicians toward prescribing may be characterized as falling along a spectrum between pharmacologic Calvinism and psychotropic hedonism, reflecting a personal and moral stance toward prescribing medication for the relief of psychic distress. The abundant literature on anti-anxiety agents falls short of providing reliable measures for diagnosis and prescribing. Given the ubiquity of anxiety in hospital settings, the physician must frequently confront the question of whether to prescribe. The use of a benzodiazepine for the distressed, anxious patient is often a therapeutic act analogous to the provision of pain relief. When compared with barbiturates and non-barbiturate sedative and hypnotic agents (meprobamate, ethchlorvynol, glutethimide, methaqualone, and others), the benzodiazepines are more selectively anxiolytic, with less sedation and less morbidity and mortality in overdose and acute withdrawal. Because using a benzodiazepine represents a clinical decision to offer symptomatic relief, the critical clinical assessment is to evaluate the patient's response. The patient's coping should be enhanced in addition to, and as a consequence of, relief from suffering. Choice of Benzodiazepine All available benzodiazepines are effective in treating generalized anxiety. Drug selection is based on pharmacokinetic properties, which determine the rapidity of onset of effect, the degree of accumulation with multi-dosing, the rapidity of offset of clinical effect, and the risk of drug discontinuation syndrome. For single or acute dosing, the onset of effect is determined by the rate of absorption from the stomach, and the offset by distribution from plasma into lipid stores. The half-life of a drug predicts the amount of accumulation of drug in plasma with multi-dosing and the speed of washout on drug discontinuation (and thus the quickness of return of symptoms or the risk of rebound and withdrawal). For example, a rapidly absorbed, lipophilic agent, such as diazepam, given acutely, has a rapid but relatively short-lived effect; with repeated dosing, however, plasma levels are higher than for a short half-life drug at steady state. The long half-life offers some tapering effect to help protect against rebound or withdrawal on discontinuation. The clinician can choose a drug to have a fast onset for greater clinical effect, a slow onset to minimize sedation or confusion, short action to allow rapid clearing, or long action to minimize inter-dose or post-treatment rebound symptoms (Table 13-4). Treatment begins with low doses (e.g., diazepam 5 to 10 mg/day or its equivalent) and upward titration. Dosages vary, but for usual situational anxiety, 30 to 40 mg of diazepam a day or its equivalent are not usually exceeded. TABLE 13-4 Characteristics of Commonly Used Benzodiazepines 417 DRUG HALF-LIFE (h) DOSAGE EQUIVALENT (mg) ONSET SIGNIFICANT METABOLITES TYPICAL ROUTE OF ADMINISTRATION Midazolam (Versed) 1–12 2.0 Fast No IV, IM Oxazepam (Serax) 5–15 15 Slow No PO Lorazepam (Ativan) 10–20 1.0 Intermediate No IV, IM, PO Alprazolam (Xanax)a 12–15 0.5 Intermediatefast No PO Chlordiazepoxide (Librium) 5–30 10 Intermediate Yes PO, IV Clonazepam (Klonopin)a 15–50 0.25 Intermediate No PO Diazepam (Valium) 20–100 5.0 Fast Yes PO, IV Flurazepam (Dalmane) 40 15.0 Fast Yes PO Clorazepate (Tranxene) 30–200 7.5 Fast Yes PO aCommonly used to treat panic disorder. Patients in whom benzodiazepine therapy is being prescribed to manage acute situational reactions should expect that treatment will be of limited duration. For specific phobic anxiety (e.g., fear of flying), occasional use is indicated. For generalized anxiety, using anxiolytics for periods of exacerbation may be effective, although increasing recognition of the distress and chronicity associated with persistent anxiety has underscored the observation that many patients often report sustained improvement and improved quality of life with maintenance treatment. Precautions in Prescribing A withdrawal syndrome, usually mild but potentially severe depending on the dose and the duration of treatment, may follow abrupt cessation of therapy. For patients receiving usual doses for less than 3 to 4 weeks—during hospitalization, for example—without prior use of sedatives, the risk of an abstinence syndrome is less. In general, however, treatment is discontinued by tapering doses, gradually adjusting decrements according to patient response. Over-use of medication and drug-seeking from multiple sources is a concern for outpatient prescribing, but with the controlled use of drugs in the hospital, particular vigilance is appropriate primarily for the patient with a history of drug or alcohol abuse. The sedative effects of benzodiazepines are additive with those of other CNS depressants, and plasma levels are higher with the use of certain drugs, such as cimetidine. A few patients, particularly with use of HPBs, are prone to increased hostility, aggression, and rage eruptions. Pharmacologic Alternatives to Benzodiazepines Anticonvulsants (including valproate, gabapentin, topiramate, and lamotrigine) are increasingly being studied and used for a range of anxiety disorders, with some (e.g., gabapentin) administered as an alternative to benzodiazepines because of their sedating properties and tolerability.114 Although typical neuroleptics (e.g., trifluoperazine) have long been used in clinical practice for the treatment of anxiety, concerns about extrapyramidal effects and tardive dyskinesia have limited this practice. Based on accruing open-label reports and controlled studies, the atypical neuroleptics also appear to have anxiolytic effects across a variety of conditions.115 However, although less likely to be associated with neurologic side effects 418 (e.g., extrapyramidal symptoms, tardive dyskinesia) than older-generation agents,116 the severity of potential metabolic consequences (e.g., weight gain, diabetes, increased triglycerides) associated with these agents suggests that caution must be taken when prescribing them. β-Blocking drugs, such as propranolol hydrochloride, have proved useful in alleviating some of the peripheral autonomic symptoms of anxiety (such as tremor and tachycardia). Although of second-line or third-line importance in treating panic attacks or more cognitively experienced symptoms (e.g., worry), β-blockers are often impressively useful in the performance-anxiety subtype of social phobia and when persistent peripheral symptoms (somatic anxiety) predominate. Agents, such as atenolol, that are less able to cross the blood– brain barrier than propranolol may have advantages for patients who experience fatigue or dysphoria when taking propranolol. Effective doses vary, and treatment requires upward titration from low initial doses. Buspirone is a non-benzodiazepine anxiolytic without sedative and anticonvulsant properties or abuse potential. It interacts with postsynaptic 5-HT (serotonin) receptors as a partial agonist and with dopamine receptors but apparently not with the benzodiazepine-GABA receptor.116 Buspirone is ineffective in panic disorder, and although clinical trials suggest that it is effective for the treatment of GAD, many clinicians and patients have found it disappointing for this indication as well. For some patients, this may in part result from a latency of therapeutic response of weeks, similar to the antidepressants, and the presence of a critical beneficial dose threshold. The dosage range is 5 to 20 mg three times a day. Cognitive-behavioral Therapy For patients with persisting anxiety symptoms, cognitive-behavioral strategies similar to those used for ambulatory patients with anxiety disorders may be adapted to the hospitalized medical patient. CBT for anxiety disorders brings to bear an array of cognitive re-structuring, exposure, and symptom management techniques that target the core fears and behavioral pattern characterizing each anxiety disorder. Cognitive interventions include a variety of procedures to challenge and re-structure the inaccurate and maladaptive cognitions that increase anxiety and help maintain anxiety disorders. Procedures range from informational discussions, self-monitoring, and Socratic questioning to the construction of behavioral experiments in which patients can directly examine the veracity of anxiogenic expectations. A reliance on corrective experiences also lies at the heart of exposure interventions that provide patients with opportunities to extinguish learned fears, by directly confronting (in a hierarchical fashion) feared events and sensations. Symptom management techniques typically include relaxation and breathing re-training procedures to help eliminate anxiogenic bodily reactions. In addition, training in problemsolving or social skills may be necessary to eliminate behavioral deficits hat help maintain anxiety disorders. Similarly, couples sessions may be required to change family patterns that help maintain avoidant or other anxiety-related 419 behaviors. CBT centers on the elimination of core features of each disorder, with treatment for panic disorder targeting fears of arousal, anxiety, and panic symptoms; treatment for social phobia targeting fears of negative evaluations by others; and treatment for PTSD targeting fears of cues of the traumatic event, including fears of the memory and anxiety symptoms accompanying the memory of the trauma. Treatment for GAD focuses on the aberrant worry process itself but also includes symptom management procedures, and treatment for OCD focuses on breaking the link between intrusive thoughts, anxiety, and compulsive behaviors using exposure techniques combined with compulsion-response prevention. The success of these strategies has made them among the most promising in the treatment literature, with the efficacy of CBT equaling or surpassing that of alternative treatments.97,117–121 Nonetheless, referral for CBT may be limited by the availability of clinicians specializing in these methods. In addition, the hospital setting may not allow timely initiation of treatment or the completion of basic treatment packages. Basic treatment interventions are commonly delivered in a series of 12 to 16 sessions, although patients may respond much earlier. For patients unresponsive, uninterested, or unwilling to make the initial time investment required for CBT, pharmacotherapy offers the most efficacious alternative. 420 References 1. Craske MG, Stein MB. Anxiety. Lancet. 2016;388(10063):3048–3059. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association: Washington, DC; 2013. 3. Robins LN, Helzer JE, Weissman MM, et al. Lifetime prevalence of specific psychiatric disorders in three sites. Arch Gen Psychiatry. 1984;41(10):949–958. 4. Mackenzie TB, Popkin MK. Organic anxiety syndrome. Am J Psychiatry. 1983;140(3):342–