There is limited systematic data assessing alternate pharmacotherapy of social anxiety disorder in patients failing to tolerate or fully respond to initial treatment; no data specifically address the efficacy of citalopram in this scenario. We present a prospective open-label trial of citalopram in 10 patients with generalized social anxiety disorder, 6 of 10 of whom had not responded to or not tolerated a prior treatment intervention for the disorder. Citalopram, at a mean dose of 55 mg (SD+12.7 mg) was well tolerated, and patients improved significantly on all outcome measures. Results of this study suggest that citalopram may be a safe and effective treatment for generalized social anxiety disorder, including patients who have failed to tolerate or respond to a prior treatment trial.

What are the current recommendations for the long-term treatment of generalized anxiety disorder (GAD)? GAD is a common disorder with a lifetime prevalence of 4% to 7% in the general population. GAD is characterized by excessive, uncontrollable worry or anxiety about a number of events or activities that the individual experiences on more days than not over a 6-month period. Onset of GAD symptoms usually occurs during an individual's early twenties; however, high rates of GAD have also been seen in children and adolescents. The clinical course of GAD is often chronic, with 40% of patients reporting illness lasting >5 years. GAD is associated with pronounced functional impairment, resulting in decreased vocational function and reduced quality of life. Patients with GAD tend to be high users of outpatient medical care, which contributes significantly to healtcare costs. Currently, benzodiazepines and buspirone are prescribed frequently to treat GAD. Although both show efficacy in acute treatment trials, few long-term studies have been perform Benzodiazepines are not recommended for long-term treatment of GAD, due to associated development of tolerance, psychomotor impairment, cognitive and memory changes, physical dependence, and a withdrawal reaction on discontinuation. The antidepressant venlafaxine extended-release (XR) has received approval for the treatment of GAD in the United States and many other countries. Venlafaxine XR has demonstrated efficacy over placebo in two randomized treatment trials of 6 months' duration as well as in other acute trials. Paroxetine is the first of the selective serotonin reuptake inhibitors (SSRIs) to receive US approval for the treatment of GAD. Paroxetine demonstrated superiority to placebo in short-term trials, and investigations into the use of other SSRIs are ongoing. This suggests that other SSRIs, and serotonin and noradrenaline reuptake inhibitors, are likely to be effective in the treatment of GAD. Of the psychological therapies, cognitive-behavioral therapy (CBT) shows the greatest benefit in treating GAD patients. Treatment gains after a 12-week course of CBT may be maintained for up to 1 year. Currently, no guidelines exist for the long-term treatment of GAD.

Anxiety disorders are highly prevalent, are increasing in incidence, affect individuals early in life, and significantly impact health care and quality of life. As such, they are serious public health problems that deserve attention now and in the future. Over the last 10–20 years, there has been marked improvement in pharmacologic and psychosocial interventions for anxiety. Due to their broad spectrum of efficacy against common comorbidities and lack of association with abuse and dependence, serotonergic and mixed serotonergic noradrenergic antidepressants are first-line therapies for anxiety disorders. Benzodiazepines are still widely used in clinical practice because they are well tolerated and work quickly and effectively. Other medications that are emerging as potentially useful for selected populations with anxiety include atypical neuroleptics and anticonvulsants. Cognitive-behavioral therapy (CBT) is at least as effective as medication for many patients with anxiety disorders and facilitates maintenance of benefit over the long term. Resilience, the capacity to bounce back from adversity, can be reliably measured with a psychometrically valid scale, the Connor-Davidson Resilience Scale. Compared with the general population, individuals with anxiety disorders exhibit decreased resilience. Studies have shown that pharmacologic treatment combined with CBT may increase resilience within 2–3 months. Emerging neurobiologic research indicates that noradrenergic pathways and 5-HT2 transporter efficiency may mediate effects on resiliency.

Attempts to understand the underlying etiology of panic disorder have, at times, oscillated between reductionistic biologic or psychologic characterizations that have put pharmacotherapists and cognitive-behavioral therapists on opposite sides of a fence with patients caught in the middle. However, research emerging over the last couple of decades is pointing to a more complex interplay between dysregulated neurobiological systems and psychological factors that influence the manifestations of fear and anxiety and permit a more nuanced view of the etiology of panic disorder while pointing to potential rational strategies for treating patients. The articles in this supplement explore a range of explanatory models relevant to the underlying etiology of panic disorder, and then focus on treatment, including pharmacologic agents, and a paradigm in which cognitive-behavioral therapy (CBT) can be efficiently and effectively integrated with pharmacotherapy in an attempt to optimize patient care.

In the first article, David Baldwin, MB, BS, DM, FRCPsych, discusses the burden of panic disorder to patients and society; the difficulties associated with misdiagnosis and inadequate treatment; the challenges imposed by excess healthcare utilization, reduced quality of life, and psychiatric and medical comorbidity; and the implications for therapeutics.

What is the best approach for treating patients with social phobia (social anxiety disorder) over the long term? Social phobia is the most common anxiety disorder, with reported prevalence rates of up to 18.7%. Social phobia is characterized by a marked and persistent fear of being observed or evaluated by others in social performance or interaction situations and is associated with physical, cognitive, and behavioral (ie, avoidance) symptoms. The onset of social phobia typically occurs in childhood or adolescence and the clinical course, if left untreated, is usually chronic, unremitting, and associated with significant functional impairment. Social phobia exhibits a high degree of comorbidity with other psychiatric disorders, including mood disorders, anxiety disorders, and substance abuse/dependence. Few people with social phobia seek professional help despite the existence of beneficial treatment approaches. The efficacy, tolerability, and safety of the selective serotonin reuptake inhibitors (SSRIs), evidenced in randomized clinical trials, support these agents as first-line treatment. The benzodiazepine clonazepam and certain monoamine oxidase inhibitors (representing both reversible and nonreversible inhibitors) may also be of benefit. Treatment of social phobia may need to be continued for several months to consolidate response and achieve full remission. The SSRIs have shown benefit in longterm treatment trials, while long-term treatment data from clinical studies of clonazepam are limited but support the drug's efficacy. There is also evidence for the effectiveness of exposure-based strategies of cognitive-behavioral therapy, and controlled studies suggest that the effects of treatment are generally maintained at long-term follow-up. In light of the chronicity and disability associated with social phobia, as well as the high relapse rate after short-term therapy, it is recommended that effective treatment be continued for at least 12 months.

Panic disorder, frequently complicated by agoraphobia in the clinical setting, is a relatively common disorder that is associated with significant morbid burden and dysfunction in affected individuals. PD treatment is focused on the reduction of panic attacks, avoidance behavior, and anticipatory anxiety, as well as the resolution of comorbid conditions, with the goal of normalizing function and improving overall quality of life. Antidepressants, including the selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors, as well as benzodiazepines, are commonly used as primary pharmacotherapies for the treatment of PD, with a variety of other novel interventions potentially useful as well, to optimize treatment outcome.

Clinical experience and systematic inquiry demonstrate that many patients with mood and anxiety disorders remain symptomatic despite standard interventions. These observations have prompted the search for alternative pharmacotherapeutic treatment options. Anticonvulsants, including valproic acid and carbamazepine, have demonstrated benefit for a number of psychiatric conditions. Recently, clinical and research attention has focused on the use of the new anticonvulsants gabapentin and lamotrigine as alternatives to standard pharmacotherapies for the treatment of mood and anxiety disorders. This paper reviews the experience to date with these agents in the treatment of psychiatric conditions. Gabapentin demonstrates promise for the treatment of panic and generalized anxiety, while both gabapentin and lamotrigine appear useful as mood stabilizers in the treatment of bipolar disorder.

Posttraumatic stress disorder (PTSD) is a common and disabling condition. In addition to combat-related PTSD, the disorder occurs in civilians exposed to severe traumatic events, with the community prevalence rate for the combined populations reaching as high as 12%. If left untreated, PTSD may continue for years after the stressor event, resulting in severe functional and emotional impairment and a dramatic reduction in quality of life, with negative economic consequences for both the sufferer and society as a whole. Although PTSD is often overlooked, diagnosis is relatively straight-forward once a triggering stressor event and the triad of persistent symptoms—reexperiencing the traumatic event, avoiding stimuli associated with the trauma, and hyperarousal—have been identified. However, comorbid conditions of anxiety and depression frequently hamper accurate diagnosis. Treatment for PTSD includes psychotherapy and pharmacotherapy. The latter includes selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and monoamine oxidase inhibitors. Only SSRls have been proven effective and safe in long-term randomized controlled trials. Current guidelines from the Expert Consensus Panel for PTSD recommend treatment of chronic PTSD for a minimum of 12–24 months.

While the public health perspective prioritizes large populations of affected individuals, our job as clinicians is to help one patient at a time. Over the last 10–20 years, there has been marked improvement in pharmacologic and psychosocial interventions available for patients with anxiety disorders (Slide 8).

The use of antidepressants, particularly the serotonergic and serotonergic noradrenergic agents, have received increased attention as first-line treatment for most of the anxiety disorders, including panic disorder, social phobia, posttraumatic stress disorder (PTSD), and generalized anxiety disorder (GAD). Antidepressants are often used as first-line therapy for anxiety disorders because of their broad spectrum of efficacy against common comorbidities, especially depression, and because of concern about benzodiazepine-associated dependence, abuse liability, and lack of efficacy for depression and other comorbidities (Slide 9).

These newer antidepressants have advantages over the older antidepressants, particularly the tricyclics and the monoamine oxidase inhibitors, in that they are generally better tolerated and more appropriate for use in potentially suicidal patients because they are less lethal in overdose. However, there are some side effects that may limit their use in some patients. In the case of the serotonergic antidepressants, many patients are hesitant to initiate or maintain treatment due to concerns about sexual dysfunction.

Although anxiety and mood disorders are listed as separate disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, they frequently coexist. They may be expressed phenotypically as comorbidities or as the provisional entity mixed anxiety-depressive disorder. Patients with both anxiety and depression are more symptomatic, use more health care resources, and have a worse prognosis than those with a single disorder. Recognizing and treating these patients are challenges for physicians because the symptoms of the two disorders often overlap. Administration of effective treatment, comprising both anxiolytic and antidepressant effects, can reduce patient distress and disability, as well as inappropriate utilization of medical services. Medications such as tricyclic antidepressants, selective serotonin reuptake inhibitors, nefazodone, venlafaxine XR (extended release) and mirtazapine, are highly effective in treating comorbid depression and anxiety. These newer agents now represent the pharmacotherapeutic treatments of choice for the comorbid conditions.

What are the symptoms of panic disorder and how is the disorder most effectively treated? One of the most commonly encountered anxiety disorders in the primary care setting, panic disorder is a chronic and debilitating illness. The core symptoms are recurrent panic attacks coupled with anticipatory anxiety and phobic avoidance, which together impair the patient's professional, social, and familial functioning. Patients with panic disorder have medically unexplained symptoms that lead to overutilization of healthcare services. Panic disorder is often comorbid with agoraphobia and major depression, and patients may be at increased risk of cardiovascular disease and, possibly, suicide. Research into the optimal treatment of this disorder has been undertaken in the past 2 decades, and numerous randomized, controlled trials have been published. Selective serotonin reuptake inhibitors have emerged as the most favorable treatment, as they have a beneficial side-effect profile, are relatively safe (even if taken in overdose), and do not produce physical dependency. High-potency benzodiazepines, reversible monoamine oxidase inhibitors, and tricyclic antidepressants, have also shown antipardc efficacy. In addition, cognitive-behavioral therapy has demonstrated efficacy in the acute and long-term treatment of panic disorder. A n integrated treatment approach that combines pharmacotherapy with cognitive-behavioral therapy may provide the best treatment. Long-term efficacy and ease of use are important considerations in treatment selection, as maintenance treatment is recommended for at least 12–24 months, and in some cases, indefinitely.