Anxiety is a state of fear or a subjective feeling of apprehension, dread or foreboding. This psychological state is often accompanied by signs of autonomic activation or other physical symptoms. Anxiety is a universal human emotion that may serve adaptive purposes, but may also be a symptom or syndrome causing suffering and disability. The task of the clinician is to determine whether an anxious patient has an anxiety disorder, whether the anxiety is a symptom of an underlying medical condition or is due to the effects of a medication or drug, or if the anxiety is an expectable reaction to a life event.

Anxiety disorders are common in primary care settings; prevalence rates of all DSM-IV anxiety disorders in primary care settings range from five percent to 21 percent, with panic disorder and generalized anxiety disorder accounting for a majority of cases.^,,, A survey administered to a systematic sample of 1007 patients with scheduled appointments at the Associates in Internal Medicine (AIM) practice found prevalences of 14.8 percent for generalized anxiety disorder and 8.3 percent for panic disorder. Patients with panic disorder have higher rates of utilization of general medical services than patients with any other psychiatric diagnosis, and have a high likelihood of having multiple medically explained symptoms. The level of overall functioning and well-being is significantly lower for patients with anxiety symptoms compared with controls, and comparable to that of patients with chronic physical disease.

The pathophysiology of anxiety disorders is not well fully understood. Animal studies have demonstrated the existence of a "fear network" involving the amygdala and its interactions with the hippocampus and the medial prefrontal cortex, thought to be important in generating conditioned fear responses. The noradrenergic, serotonergic and gamma-aminobutyric acid (GABA) neurotransmitter systems have all been implicated in the biology of anxiety. Noradrenergic neurons that originate in the locus coeruleus (LC) terminate in cortical and subcortical regions involved in the mediation of fearful behavior. In animal studies, stimulation of these LC neurons results in behaviors that mimic fear responses, while LC lesions can eliminate these fear responses. In humans, drugs that activate noradrenergic neurons (such as yohimbine) are anxiogenic, while drugs that decrease activity of LC cells (such as the tricyclic antidepressants) are anxiolytic. GABA is the major inhibitory neurotransmitter in the brain. Benzodiazepines, which are potent anxiolytic agents, bind to the GABA receptor and cause increased affinity of GABA to its receptor, leading to enhanced neuronal inhibition. The role of serotonin in anxiety is complex. Serotonergic neurons connecting the dorsal raphe and the amygdala are thought to be important in regulating anxiety. Buspirone, an anxiolytic effective in generalized anxiety disorder, has multiple effects at serotonin receptors, with an overall effect of causing a decrease in serotonin neurotransmission, while the selective serotonin reuptake inhibitors, also effective in treating anxiety disorders, cause an increase in serotonin in the synaptic cleft after chronic use. Finally, alterations in hypothalamic-pituitary-adrenal axis function are present in some anxiety disorders, such as post-traumatic stress disorder.

The biologic basis of anxiety has been most extensively studied in panic disorder. Several theoretical models exist. One theory posits that patients with panic disorder have a faulty central "suffocation alarm" mechanism, and respond to slight rises in CO2 blood levels with a sensation of suffocation, and hence, panic. Evidence supporting this model includes the observation , confirmed infrom several studies, that panic attacks can be induced in susceptible individuals (though not in normal controls) by the intravenous infusion of sodium lactate or the inhalation of five percent CO2. However, not all investigators have found evidence of CO2 hypersensitivity..⁷ A psychological theory of panic disorder postulates that panic attacks are the result of "catastrophizing" misinterpretations of bodily sensations, which can be corrected by cognitive-behavioral therapy, a form of psychotherapy whose efficacy in treating panic disorder has been documented in controlled studies. An overarching hypothesis based on recent research developments proposes that patients with panic disorder, a highly familial condition, may inherit an especially sensitive central nervous system fear mechanism, centered in the amygdala and involving the hippocampus and other areas of the brain. Medications and cognitive-behavioral therapy may act at different levels of this mechanism, both producing clinical improvement.

Diagnosis

Anxiety can manifest in a variety of ways. The DSM-IV categorizes anxiety syndromes into the following diagnoses:

Panic attacks:

A panic attack is a discrete period of intense fear or discomfort, in which four or more of the following symptoms develop abruptly and reach a peak within 10 minutes: palpitations, pounding heart, or accelerated heart rate; sweating; trembling or shaking; sensations of shortness of breath or smothering; feeling of choking; chest pain or discomfort; nausea or abdominal distress; feeling dizzy, lightheaded or faint; derealization or depersonalization; fear of losing control or going crazy; fear of dying; paresthesias; chills or hot flushes. Panic disorder is diagnosed when recurrent unexpected panic attacks occur and are accompanied by persistent concern about having additional attacks, worry about the implications of the attack or its consequences (e.g., losing control, having a heart attack, "going crazy"), or a change in behavior related to the attacks. Panic attacks may be accompanied by agoraphobia, which is anxiety about being in places or situations from which escape might be difficult or embarrassing or in which help may not be available in the event of having a panic attack. Agoraphobic fears typically involve situations such as being outside the home alone; being in a crowd, being on a bridge, or traveling in a bus, train, or automobile; these situations are avoided or else are endured with marked distress or anxiety.

Generalized anxiety:

Generalized anxiety disorder is defined by the presence of excessive anxiety and worry occurring more days than not for at least six months, about a number of events or activities. The persons finds it difficult to control the worry, and the focus of the anxiety or worry is not confined to the features of another psychiatric disorder (e.g., the anxiety or worry is not about having a panic attack). The anxiety and worry are associated with three or more of the following six symptoms: restlessness or feeling keyed-up or on edge; being easily fatigued; difficulty concentrating or mind going blank; irritability; muscle tension; or sleep disturbance.

Mixed anxiety-depression:

Though not listed as a distinct disorder in DSM-IV, criteria have been proposed for cases in which symptoms of anxiety and depression both exist, and although do not meet criteria for an established anxiety or depressive disorder, nevertheless give rise to a persistent or recurrent dysphoric mood. The dysphoric mood is accompanied by the presence of at least four or more of the following symptoms: difficulty concentrating, disturbed sleep, fatigue, irritability, worry, crying easily, hypervigilance, anticipating the worst, a sense of hopelessness, and low self-esteem or feelings of worthlessness. Mixed anxiety-depression appears to be common in primary-care settings.^1,4

A patient may develop clinically significant nervousness, worry or jitteriness in response to a life stressor or multiple stressors. Adjustment disorder with anxiety is diagnosed if the symptoms do not persist for more than 6 months after the stressor has terminated, and if the presentation does not meet criteria for another disorder, such as panic disorder.

Specific phobia:

A specific phobia is a marked and persistent fear that is excessive or unreasonable (and is recognized as such by the person) cued by the presence or anticipation of a specific object or situation (e.g., flying, heights, animals). Exposure to the phobic stimulus almost invariably provokes an immediate anxiety response, which may take the form of a situationally bound or situationally predisposed panic attack.

Social phobia:

A marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. The person fears that he or she will act in a way that will be humiliating or embarrassing, but recognizes that this fear is excessive or unreasonable. People with social phobia may fear even common social situations such as speaking in the presence of even one or a small number of unfamiliar people, eating in public places, or using public restrooms.

Obsessive-compulsive disorder:

Patients with this disorder have either obsessions or compulsions (though not necessarily both). Obsessions are recurrent, persistent thoughts, impulses, or images that are experienced as intrusive and inappropriate, and that caused marked anxiety or distress. These thoughts, impulses or images are not simply excessive worries about real-life problems. The person recognizes them as products of his or her own mind and attempts to ignore or suppress them, or to neutralize them with some other thought or action. Compulsions are repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., counting, praying, repeating words) that the person feels driven to perform in response to an obsession, or according to rigidly applied rules. The obsessions or compulsions cause marked distress, and are time consuming, and significantly interfere with the person’s normal routine, occupational functioning, or usual social activities or relationships. The person recognizes that the obsessions or compulsions are excessive or unreasonable.

Exposure to events that involve actual or threatened death or serious injury, or a threat to the physical integrity of self or others, may be followed by reactions characterized by dissociation (e.g., "being in a daze" or feeling numb or detached or unreal), reexperiencing of the trauma (e.g., dreams, flashbacks), avoidance of stimuli that trigger recollection of the trauma, and anxiety or increased arousal. Such reactions may be acute and self-limited or may become chronic. They may also have a delayed onset.

A number of medical and other psychiatric disorders may cause or exacerbate anxiety, and must be distinguished from anxiety disorders. Medical disorders to consider include cardiac disease (e.g., arrhythmias), chronic obstructive pulmonary disease, endocrine disorders (e.g., hyperthyroidism, hypoglycemia), pheochromocytoma, and vestibular disturbances. Medications that can cause anxiety include beta-adrenergic agonists, decongestants, stimulants, and serotonin-reuptake inhibitors. The phenothiazines and related drugs, including metoclopramide (Reglan™) and prochlorperazine (Compazine™) may cause akathisia, a side-effect characterized by an inner sense of restlessness and agitation, which may be confused with anxiety. Physicians should inquire about caffeine use, as well as alcohol and substance abuse.

Psychiatric disorders which should be considered in the differential diagnosis of anxiety include affective disorders (depression, mania), psychotic disorders, hypochondriasis or other somatoform disorders, attention-deficit/hyperactivity disorder, and severe personality disorders (e.g., borderline personality disorder). There is a high degree of comorbidity between depression and anxiety disorders, and one should always inquire about depressive symptoms in patients presenting with anxiety.

In patients complaining of anxiety, the following questions are useful in establishing a diagnosis.

5. Did the anxiety symptoms develop following a traumatic event? If so, consider post-traumatic stress disorder.
6. Does the patient feel depressed or anhedonic as well as anxious? If so, consider

major depression or mixed anxiety-depression.

7. Did the anxiety symptoms develop in response to a stressor or stressors and not meet criteria for any of the above anxiety disorders? If so, consider adjustment disorder with anxiety.

Non-specific therapeutic interventions may be helpful in all patients complaining of anxiety. Patient education is important. The anxiety diagnosis should be explained, as should the connection between states of anxiety or tension and particular physical symptoms. A careful review should be done of all medications, drugs and alcohol used by the patient, including caffeine, and possible anxiogenic agents eliminated or reduced. Aerobic exercise, when done on a regular and sustained basis, has been shown to decrease anxiety symptoms. Simple relaxation techniques, such as diaphragmatic breathing and progressive muscle relaxation, can be easily taught to patients.

Panic disorder: The treatment of panic disorder is aimed at eliminating panic attacks, as well as any associated agoraphobia or anticipatory anxiety. Useful medications include the tricyclic antidepressants, the selective serotonin reuptake inhibitor antidepressants (SSRIs), the tricyclic antidepressants (TCAs), and high potency benzodiazepines. The tricyclic and serotonin reuptake inhibitor antidepressants are the preferred initial treatments given their safety, favorable side effect profile, and possible superior efficacy; however, . Antidepressants, unlike benzodiazepines, also treat depression, often comorbid with panic disorder. However, since their onset of action may be two to four weeks. Benzodiazepines have a faster onset of efficacy, usually within a few days, and, if rapid response is needed benzodiazepines may be used either as a sole agent or as an adjunct to antidepressant therapy until the antidepressant becomes therapeutic. Benzodiazepines may also be used as a sole agent if antidepressants are ineffective, or may be combined with an antidepressant in partial responders. In addition to SSRIs and TCAs, evidence from mostly open label case series suggests that the antidepressant venlafaxine may also be an effective antipanic agent, at lower than antidepressant dosages..

The antidepressants should be initiated at low doses because patients with panic disorder are extremely sensitive to side effects such as agitation or increased anxiety (e.g., desipramine 10mg QD, fluoxetine 5mgparoxetine 5 or 10mg QD, sertraline 12.5mg or 25mg QD) , venlafaxine XR 37.5mg QD)to minimize the potential for side effects such as agitation or increased anxiety, and then slowly increased as needed to maximum antidepressant doses (see chapter on depression) until panic symptoms have been eliminated. The benzodiazepines most commonly used include alprazolam (Xanax™), starting with 0.25mg QID and increasing as needed to a maximum of 1mg QID, and clonazepam (Klonopin™), starting with 0.5mg BID and increasing to a maximum of 2mg BID. Alprazolam has a shorter half-life than clonazepam, thus necessitating more frequent dosing (which may increase non-compliance) and having a potential for rebound anxiety between doses and increased withdrawal symptoms on discontinuation.

The pharmacologic treatment of panic disorder can be divided into three phases. In the acute phase, patients need to be closely monitored, and medications are increased until panic symptoms have resolved. Benzodiazepine doses may be increased every few days, and antidepressant doses every one to two weeks. Once symptoms have been eliminated, the medication(s) should be continued at the same dose for 3 to six months, constituting the maintenance phase. If patients remain free of symptoms, a gradual reduction in medication dose may be initiated, and after 12 months of successful therapy, gradual taper and discontinuation of medication should be attempted. In patients who do not wish to take medication, in whom medication is contraindicated (e.g., in pregnancy), or whose symptoms do not respond fully to medication, consider referral to a psychiatrist or psychologist for cognitive-behavioral therapy of panic disorder, whose efficacy has been well-established. Patients with accompanying agoraphobia should be referred for cognitive-behavioral therapy, since agoraphobia has a poorer response to medications.

Generalized anxiety disorder: Although benzodiazepines were traditionally used to treat generalized anxiety disorder (GAD) The medications whose efficacy in generalized anxiety disorder has been best demonstrated are the benzodiazepines. Tand hey have the advantage of immediate effectiveness, but they cause physical dependence and may be difficult to discontinue when taken for long periods of time. Antidepressants are more appropriate first-line agents for GAD and are also effective for comorbid depression. There is growing evidence supporting the use of paroxetine and venlafaxine XR for GAD, and recent guidelines recommend choosing an SSRI, such as paxil, or venlafaxine XR as first-line agents in the treatment of this disorder. Commonly used benzodiazepines are clonazepam (0.5mg BID to 2mg BID), alprazolam (0.25mg TID to 1mg QID) and lorazepam (Ativan, 0.5mg TID to 2mg QID). The only non-benzodiazepine anxiolytic currently available is buspirone (Buspar). It does not cause physical dependence, but can take weeks to become effective. The starting dosage is 5mg TID and can be raised as needed by incremental steps of 5 mg every few days to 15mg TID. Because it does not cause dependence, it is a good choice for patients with a history of alcohol abuse.⁸ The tricyclic antidepressants may also be effective in GAD, and though their efficacy in this disorder has not been extensively studied, one well-controlled study found imipramine to be more effective than diazepam in treating GAD. Limited data awaiting further confirmation suggest that the serotonin reuptake inhibitor antidepressant paroxetine (Paxil) and the newer antidepressant Results from an open trial suggest that nefazodone (Serzone™) may also be effective in the treatment of GAD.

In patients with uncomplicated GAD (without comorbid depression or panic disorder), the non-benzodiazepine anxiolytic buspirone (Buspar™) can be used. This medication is effective for GAD but does not treat depression or panic disorder. It does not cause physical dependence, but can take weeks to become effective. The starting dosage is 7.5mg BID and can be raised as needed by incremental steps of 7.5mg every few days. Patients usually require a minimum dose of 15mg BID (maximum daily dose is 60mg/day). Because it does not cause dependence, it is a good choice for patients with a history of alcohol abuse. If choosing a benzodiazepine for a patient without a history of substance use, the more commonly used ones include clonazepam (0.5mg BID to 2mg BID), alprazolam (0.25mg TID to 1mg QID) and lorazepam (Ativan, 0.5mg TID to 2mg QID). Non-medication treatments, such as cognitive therapy, behavioral therapy, biofeedback, or relaxation techniques, have also been found to be helpful in GAD, both in reducing somatic symptoms as well as chronic anxiety.

Treatment for mixed anxiety-depression has not been well studiedis less well studied. However, patients with mixed symptoms represent the largest group in primary care. it is reasonable to assume that the The antidepressants may may be helpful, with benzodiazepines, with benzodiazepines potentially useful as an adjunct treatment. Patients with adjustment disorder with anxiety may benefit from counseling and support during office visits to help enhance their strengths and coping skills. Some patients, and may also benefit from a psychotherapy referral.

Treatment of the other anxiety disorders listed above often involves medications or therapies with which primary care physicians are not familiar, and is usually best handled by mental health specialists. Obsessive-compulsive disorder may be treated with serotonergic medications such as the SSRIs and clomipramine (a tricyclic antidepressant), and/or by cognitive-behavioral therapy. Social phobia may be treated with the monoamine oxidase inhibitors, the SSRIs, or benzodiazepines. For performance anxiety, beta-blockers (e.g., propranolol 10-40mg) taken PRN prior to the event can block the features of sympathetic arousal (tachycardia, trembling, voice cracking) that accompany the anxiety; this treatment can be carried out by primary care physicians. For post-traumatic stress disorder, Well-established treatment guidelines do not yet exist for post-traumatic stress disorder, but several studies have shown SSRIs have been shown to be useful for some of the symptoms of. PTSD in several studiesCognitive-behavioral therapy and group psychotherapy may also be of benefit.