Management of Generalized Anxiety Disorder in Primary Care: Identifying the Challenges and Unmet Needs

Management of Generalized Anxiety Disorder in Primary Care: Identifying the Challenges and Unmet Needs

Jonathan R. T. Davidson, MB, BS, FRCPsych; Douglas E. Feltner, MD; and Ashish Dugar, PhD

Background: Generalized anxiety disorder (GAD) is one of the most common psychiatric disorders in primary care, although it is often underrecognized and undertreated. GAD is chronic, disabling, and associated with other health problems. Treatment response is often unsatisfactory, but the clinical evidence base for new treatments has expanded substantially in the past decade and suggests a growing range of options for reducing the burden of GAD. The objective of this article was to review current literature on GAD and its management to provide an overview of the clinical importance of GAD in primary care and available treatments.

Data Sources: Recent studies (ie, over the past decade) on the epidemiology and treatment of GAD were identified by searching Medline using the term generalized anxiety disorder only and in combination with the terms epidemiology and treatment and for each drug class (benzodiazepines, azapirones, antidepressants, antihistamines, alpha-2-delta ligands, and antipsychotics) and for named drugs (buspirone, venlafaxine, duloxetine, fluoxetine, escitalopram, olanzapine, paroxetine, pregabalin, quetiapine, and risperidone in addition to psychological therapies and cognitive-behavioral therapy. The literature search was conducted in August 2008 for the period 1987-2009.

Study Selection: Studies were included if judged to be relevant to a review of the epidemiology and management of GAD. Articles were excluded if they were not written in English or were published more than 10 years before the literature search was conducted. A few older studies were included for which more recent research evidence was not available. Recent national and international guidelines for the management of GAD were also reviewed.

Data Extraction/Synthesis: Most currently available interventions have similar overall efficacy, and treatment choices should reflect the situation of individual patients. Important unmet needs exist for treatments (1) that work rapidly, with (2) broad spectrum benefits, (3) that can improve rates of remission and well-being, (4) are devoid of risk for withdrawal symptoms, and (5) have few if any adverse interactions with other drugs. Additional needs include (6) safer drugs for the elderly, (7) safe and effective drugs for children with GAD, (8) further evaluation of psychotherapy, and (9) understanding the appropriate circumstances for, and optimal choices of, drug combination.

Conclusion: While the development of novel treatments evolves, current management approaches can focus on improving identification and defining optimal use of available therapies for GAD.

Prim Care Companion J Clin Psychiatry 2010;12(2):e1-e13

© Copyright 2010 Physicians Postgraduate Press, Inc.

Submitted: December 23, 2008; accepted April 24, 2009.

Published online: March 4, 2010 (doi:10.4088/PCC.09r00772blu).

Corresponding author: Jonathan R. T. Davidson, MB, BS, FRCPsych, 3068 Baywood Dr, Seabrook Island, SC 29455 ([email protected]).

Anxiety disorders are the most prevalent of all psychiatric disorders, with generalized anxiety disorder (GAD) being the most common disorder to be seen in the primary care setting.1 Despite this, it is a diagnosis that can easily be missed, although the condition is responsive to treatment.2 The research base for the management of this disorder has expanded rapidly over the past decade, and it is the goal of this review to draw attention to this literature.

METHOD

Search Strategy and Selection Criteria

Recent studies (ie, over the past decade) on the epidemiology and treatment of GAD were identified by searching Medline using the term generalized anxiety disorder only and in combination with the terms epidemiology and treatment and for each drug class (benzodiazepines, azapirones, antidepressants, antihistamines, alpha-2-delta ligands, and antipsychotics) and for named drugs (buspirone, venlafaxine, duloxetine, fluoxetine, escitalopram, olanzapine, paroxetine, pregabalin, quetiapine, and risperidone in addition to psychological therapies and cognitive-behavioral therapy. The literature search was conducted in August 2008 for the period 1987-2009. Articles were excluded if they were not written in English or were published more than 10 years before the literature search was conducted. A few older studies were included for which more recent research evidence was not available. Recent national and international guidelines for the management of GAD were also reviewed. Relevant articles were identified by this strategy and are reviewed here.

Definition, Epidemiology, Comorbidity, and Burden of GAD

Nearly 8% of patients consulting a primary care physician have GAD according to a 6-month prevalence rate reported in a World Health Organization (WHO) study in 14 countries, including the United States.3,4 Estimates of the lifetime prevalence for the condition vary, but studies suggest it is about 5%-6% using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria5; however, the European Study of the Epidemiology of Mental Disorders (ESEMeD) gives a lower estimate of 2.8%.6 Although prevalence estimates in the ESEMeD surveys are roughly comparable with earlier studies, it has been suggested that underestimation of some prevalence rates might have occurred due to methodological features of the ESEMeD, including the way the diagnostic interviews were conducted.7 GAD is reported around twice as often in women as in men1,6 and is more commonly seen in middle age, with prevalence rates rising after the age of 35 years in women and 45 years in men.3 GAD is believed to be common in the elderly, with estimates as high as 7.3% being reported.8

The main diagnostic criteria of GAD are excessive anxiety and worry that is difficult to control along with at least 3 from a list of 6 symptoms (restlessness, irritability, difficulty concentrating, muscle tension, sleep disturbances, and being easily fatigued) and duration of the disorder for at least 6 months. Symptoms must be distressing or impairing and not adequately explained by another related disorder.9,10 By contrast, the diagnostic criteria in the Tenth Edition of the International Classification of Diseases (ICD-10)10 place greater emphasis on the presence of somatic symptoms, a difference that is noted in the International Psychopharmacology Algorithm Project (IPAP) GAD Algorithm,11,12 as it is somatic symptoms that often serve as the presenting complaint. Broadening of the definition of GAD is being considered for the next major revision of the DSM (DSM-V), expected to be published in 2012.13 To take into account the latest genetic, epidemiologic, and other research findings, the task force is considering whether GAD and major depressive disorders are different forms of the same disorder, closely related or distantly related disorders. Furthermore, amendment of the requirement for 6 months’ duration of symptoms and the primacy of persistent worry are also under consideration, as well as the number of symptoms within the definition.

The onset of GAD is usually gradual, and the condition is generally recurrent and chronic in nature. Although GAD tends to fluctuate in severity, the chances of complete recovery are low.14 The Primary Care Anxiety Project (PCAP), a longitudinal study of 539 primary care patients with anxiety disorders, has shown that GAD is a chronic and persistent illness.15 In a subsample of 113 patients who met DSM-IV criteria for GAD, only 44 patients (39%) recovered fully during 2-year follow-up, with the remainder showing no recovery (28%) or only partial recovery (33%). Furthermore, people with GAD experience impaired social functioning and quality of life16 and disability equivalent to that observed in major depression.1,17

GAD is frequently associated with other psychiatric conditions such as other mood or anxiety disorders,18,19 somatoform/pain disorders,20 medically unexplained symptoms,21 and substance use disorders.19,20,22 Another analysis of patients in the PCAP showed a high rate of psychiatric comorbidity in patients with GAD, with 61% having multiple anxiety disorders and 79% with more than 1 Axis I disorder.23

GAD has also been linked with medical disorders such as heart disease and gastrointestinal and chronic pain disorders.24-27 These associations are important at a clinical level, because patients with psychiatric or medical comorbidities have an extended clinical course and poorer outcome than patients with GAD alone.28 The PCAP has shown that the course of anxiety disorders is adversely affected by the presence of pain.29 In the subgroup of patients with GAD, the presence of back pain was associated with a reduced chance of remission. Patients with comorbidities therefore present a greater treatment challenge and need for either novel treatments or the combination of different treatment approaches, such as polypharmacy with drugs of different classes or additional nonpharmacologic approaches.

GAD is often unrecognized or misdiagnosed as a physical condition due to the range of clinical presentations, including somatic symptoms, and the frequent occurrence of comorbid conditions. Data from the PCAP showed that almost half (47%) of patients with anxiety disorders were untreated, although results for GAD were not presented.30 The main reasons for nontreatment of anxiety disorders with pharmacotherapies were that the doctors did not recommend treatment (39%) and that patients did not believe that medication was appropriate for emotional problems (37%). Similarly, the most common reasons for patients not receiving psychotherapies were that they did not believe that psychotherapy would be helpful for them (28%) or that the patients did not think that they had a treatable problem (24%). These data highlight the importance of ongoing education in this field for primary care practitioners and of informing patients of the nature of their condition and recommended treatments. When patients did receive treatment, the most common approach involved a combination of medication and psychotherapy (25% of the entire sample), with 21% receiving medication alone and 7% receiving psychotherapy alone.

In another primary care survey, the diagnosis of GAD was made in only 34% of actual GAD cases and only 20% were receiving treatment.2 Once the condition had been recognized, the treatment rate increased to 44%-60%, suggesting that enhanced recognition of GAD leads to more frequent initiation of treatment. The likelihood of a diagnosis of GAD is also influenced by the way the patient presents to the primary care physician. One study, in patients with depression or anxiety, has shown that patients who “normalize” their symptoms (ie, attribute symptoms to a nonpathologic cause, for example, explaining the symptom of fatigue by inadequate levels of exercise or overexertion) are less likely to receive a diagnosis of an anxiety disorder than those who adopt a more “psychologizing” style (ie, view their symptoms in terms of their psychological state, for example, attributing fatigue to emotional exhaustion).31

According to information gathered by the Midlife Development in the United States survey,32 and as separately reported elsewhere,33 GAD was associated with noticeable per capita work impairment days.

Treatment Goals

The treatment plan for GAD should account for (1) predominant symptoms, (2) severity of the condition, (3) presence of concomitant medical illness, (4) complications such as substance abuse or the risk of suicide, (5) outcomes of any previous treatments, (6) cost issues, (7) availability of treatment in a given area, and (8) patient preferences.34 The overall aims of treatment are 4-fold: (1) to reduce the core symptoms of GAD (both the psychic and somatic), including restoration of sleep; (2) to improve patient function and quality of life; (3) to treat comorbid disorders—present at the time of diagnosis and those that appear over the long term; and (4) to continue treatment for long enough to produce remission and, where possible, prevent relapse.

Treatment of core symptoms of GAD. Patients with GAD are generally managed in the primary care setting, and a range of pharmacologic and nonpharmacologic treatment options are available. Most patients will receive drug treatment with or without psychological therapy. The choice of drug(s) will depend on the severity of GAD; other comorbidity, including depression and insomnia; an assessment of the adverse effects; possible drug-drug interactions and other risks; and the need for an early onset of action.

GAD can often precede, and is a risk factor of, the development of depression.3 There are suggestions that pharmacotherapy for GAD can result in lower rates of depression among susceptible people.3,35 Timing of an intervention may be important in that delayed treatment of GAD may result in poorer clinical outcomes compared with patients treated within a year of the onset of symptoms.36

Improvement of patient function and quality of life. Recovery implies not only the relief of symptoms but also restoration of patients to their previous high level of functioning, including resumption of family, social, and work-related roles; however, in some lifelong cases of GAD, recovery sometimes produces a level of well-being that had never been previously experienced and that is far better than the premorbid baseline. Patients with GAD are likely to need help with managing insomnia, which can have a substantial impact on quality of life and function at work. While rapid symptom relief is desirable, the more important issue is to inform patients that persistence with therapy is necessary to achieve maximum benefit and to ensure a sustained improvement in their condition. Remission may not occur until 4-6 months into treatment.37

Treatments for GAD

The main treatment approaches for GAD comprise pharmacotherapy or psychotherapy or a combination of both. The often chronic and disabling nature of GAD means that some individuals may fail to respond fully to first-line treatment.34,38 Patients may therefore require a sequential trial of treatments or possibly the use of combination therapy.

In addition to published trials in this area, which will be reviewed below, clinical practice can be informed by the guidelines of various consensus groups, in particular those of the following:

‘ ¢ International Psychopharmacology Algorithm Project (IPAP)11,12

‘ ¢ Canadian Clinical Practice Guidelines for the Management of Anxiety Disorders39

‘ ¢ British Association for Psychopharmacology (BAP)38

‘ ¢ World Federation of Societies of Biologic Psychiatry (WFSBP)34

‘ ¢ International Consensus Group on Depression and Anxiety40

‘ ¢ National Institute for Clinical Excellence (NICE) in the UK41

While all the above guidelines are evidence based, they vary with respect to purpose and clinical utility. Some are government driven for cost-containment purposes, have little practitioner input, and offer limited clinical advice (eg, NICE), whereas others (eg, BAP, Canadian guidelines, and WFSBP) are driven mainly by a clinical practice perspective. The IPAP guidelines are unique in offering a web-based algorithm specifically for clinical situations and questions.

Pharmacologic Therapies: Short-Term Efficacy

Short-term (ie, 4-12 weeks) placebo-controlled trials have consistently shown that the following drug groups are efficacious in GAD: benzodiazepines, azapirones (buspirone), antihistamines (hydroxyzine), and 4 different types of antidepressant. However, there have been few direct comparisons between different drug classes. Therefore, the relative merits of various agents are generally established by means of (1) comparative studies, to the extent that they have been conducted; (2) extrapolation from the various 2-arm placebo-controlled trials of each drug; (3) extrapolation of knowledge obtained from other disorders (eg, side effect profiles in depression); and (4) textbooks and recommendations of consensus groups (Table 1).

Benzodiazepines. Historically, benzodiazepines have been widely used in the management of anxiety disorders.42 Their presumed mechanism of action rests in their ability to modulate the γ-amino-butyric acid (GABA) receptor and indirectly promote GABA activity. They have a rapid onset of action and are effective in GAD. While benzodiazepines improve the core symptoms of GAD, they are not recommended as monotherapy for depression, dysthymia, obsessive-compulsive disorder, and posttraumatic stress disorder, which commonly occur with GAD.40,43 However, benzodiazepines can be effective for panic44 and social anxiety disorders,45 as well as for insomnia,42,46 a symptom that is commonly associated with GAD. According to the Canadian guidelines, benzodiazepines also have a role in the management of severe GAD, or GAD with comorbid panic disorder, wherein the rapid onset of action can be useful. In these cases, benzodiazepines are often recommended as adjunctive therapy to help patients in acute crisis or while waiting for a selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) to take effect.39

However, benzodiazepine use can be problematic, particularly in older people, due to side effects such as falls, memory impairment, incoordination, drowsiness, and confusion.47 Benzodiazepines can disrupt sleep architecture, and rebound insomnia may occur after stopping treatment.48 Benzodiazepine withdrawal is also associated with distressing symptoms, which although commonly observed in patients treated with benzodiazepines for 6 months or longer, can appear earlier in the course of treatment.49 Even if benzodiazepine therapy is tapered gradually, patients can experience prolonged (for several months) anxiety, insomnia, and depression.48 Furthermore, at least 1 author claims that around a third of long-term users of these drugs experience withdrawal effects, even after tapered withdrawal of the drug.50 It is important to note that no benzodiazepine has GAD listed in its prescribing information as an indication for therapeutic use. There has been some controversy about possible cognitive impairment from long-term use of benzodiazepines in GAD. Benzodiazepines cannot be entirely exonerated in this regard, but, in general, the risk is low (possibly lower than the risk of inadequately treated GAD) and is influenced by dose and age (ie, somewhat more likely at high doses and in older people).51

Benzodiazepines also have modest abuse potential52 and should not generally be administered to patients with a history of misuse of these drugs.34 There are some circumstances for which benzodiazepine use is justified in this population, but the use of another drug with less abuse potential should be considered first as an alternative. In this type of clinical situation, the primary care physician may decide to refer the patient to a psychiatrist or addiction specialist.

Benzodiazepines may interact adversely with other drugs, including hypnotics, sedating antidepressants, opiate analgesics, anticonvulsants, antihistamines, and alcohol.48,52 Interactions with drugs that either inhibit or induce certain cytochrome P450 isoenzymes can also pose problems.

Benzodiazepines are generally recommended only for short-term use39 and are not recommended for first-line long-term treatment of GAD,39 although they have a role in the management of acute anxiety34,40 and may have a role in some cases in which somatic symptoms are more prominent than psychic symptoms.12 Despite these recommendations, benzodiazepine use remains widespread, perhaps reflecting the complexity and tenacity of GAD, as well as intolerance in some patients to SSRIs/SNRIs. In some conditions, because GAD waxes and wanes, benzodiazepines may be useful on an intermittent basis to supplement other more long-term treatments.

Other GABAergic drugs. The selective GABA reuptake inhibitor tiagabine has been studied in 3 large placebo-controlled trials, which enrolled 1,830 patients with GAD and showed no significant difference from placebo.53 Moreover, side effects were troublesome and the drop-out rate for patients taking the drug was as high as 47%. On the basis of this evidence, it seems hard to justify the use of tiagabine for GAD.

Antidepressants. The following antidepressants have demonstrated efficacy in GAD relative to placebo: SSRIs, SNRIs, tricyclic antidepressants (TCAs, particularly imipramine), and, in a single controlled trial, trazodone. Several analyses have shown similar efficacy among antidepressant agents in the management of GAD.38,54 Of these, SSRIs and SNRIs are generally preferred as first-line therapy, as the evidence supporting their efficacy is more robust, and they are usually better tolerated than the other classes of antidepressants.38,41

Paroxetine has been shown to be efficacious in GAD; however, the US Food and Drug Administration (FDA) labeling for its use in pregnancy was reclassified to category D (ie, positive evidence of risk) due to reports55 that it was associated with an increased risk of congenital malformations, especially septal defects, when used during the first trimester of pregnancy. A more recent prospective report failed to confirm this association, so the extent of actual risk is still not completely understood.56 More recently, sertraline has been shown to be efficacious in GAD,57-59 and citalopram has demonstrated efficacy in older patients (≥ 60 years of age) with GAD.60

Although the SSRIs are well tolerated, these agents are nonetheless associated with a range of adverse effects, including gastrointestinal symptoms, somnolence, disrupted sleep, and agitation.61,62 Weight gain and sexual side effects can also occur and can persist during the treatment period.63,64 The prevalence of sexual dysfunction has been estimated to be as high as 40% during treatment with SSRIs and SNRIs.65 Clayton et al66 have shown a high rate of limited sexual dysfunction in a specific phase (eg, desire, arousal, or orgasm) even when global function (ie, all phases together) was not measurably impaired from SSRI antidepressants, so the clinician may need to obtain a more detailed history addressing the various aspects of sexual function before ruling out the occurrence of the drug-induced sexual dysfunction.

As noted, GAD often occurs in the elderly, therefore, it is important to keep in mind the possibility of less common but potentially serious or even life-threatening side effects of SSRIs in this age group. Possible concerns exist over the increased risk of bleeding with SSRIs,67 reduced femoral bone density in women, and increased risk of falls.68 Inappropriate antidiuretic hormone excretion in the elderly may be as high as 12%-39% in patients receiving SSRI or SNRI treatment.69 The resultant hyponatremia can lead to misdiagnosis or misattribution (eg, fatigue, confusion) and serious consequences.

Side effects of SSRIs and SNRIs (eg, insomnia, agitation, tremor, and anxiety with SSRIs or SNRIs)61,62 add to the symptom burden of patients with GAD and are a common reason for treatment discontinuation in depression, and it is likely that a similar situation exists for GAD.70 Withdrawal symptoms from SSRIs/SNRIs are not uncommon (except for fluoxetine, which has a prolonged elimination half-life).38,71

In 2005, the FDA issued a black box label warning stating that short-term studies of major depressive disorder and other psychiatric indications have shown that antidepressant drugs can increase the risk of suicidal thinking and behavior in children and adolescents. While noting that depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide, the warning was extended in 2007 to young adults aged 18-24 years with clarification that there is no change in risk for adults aged 25-64 years and a reduction in risk for elderly adults (aged 65 years and over).72-76 This labeling was controversial,77 particularly because of the concern that reduced prescribing of antidepressants for mental disorders might lead to increases in suicide due to undertreatment, as may in fact have happened.78,79 Although the majority of the trials in the FDA analysis involved patients with depression, the FDA warning was applied to the antidepressant drugs, not to a specific indication.

The SNRIs venlafaxine and duloxetine are also effective in the treatment of GAD.80-84 The adverse effects include those associated with the SSRIs, as well as orthostatic hypotension, increased blood pressure, sweating, and urinary hesitancy. Patients taking venlafaxine or duloxetine should be monitored for increases in blood pressure.85 Both venlafaxine86 and duloxetine87 are associated with discontinuation symptoms and serious toxicity in overdose,88,89 although these problems are by no means unique to the SNRI class and should be kept in mind for all antidepressants.

The tricyclic drug imipramine is effective in GAD but is associated with the usual range of tricyclic antidepressant side effects, which limits its use for those who have not responded to an SSRI or SNRI.38,40 Another possible second-line antidepressant12 includes trazodone.90

Buspirone. Buspirone, an azapirone that acts as a partial agonist at the 5HT1a receptor, is effective for the treatment of GAD91 though may be less effective than the benzodiazepines.92-94 A recent review of 36 short-term studies95 that included 5,908 patients concluded that azapirones, including buspirone, were useful in GAD, although the drugs were less effective than the benzodiazepines. Common side effects of buspirone included drowsiness, dizziness, and nausea. Furthermore, buspirone has a slow onset of action, variable tolerability, and overall lack of benefit against most comorbid conditions. For these reasons, buspirone is not recommended as first-line treatment for GAD.12,34,40 Other azapirones (ipsapirone, gepirone, tandospirone) have been studied as GAD treatments, but none have been approved for GAD in the United States.

Antihistamines. Hydroxyzine is an H1 antagonist that has been reported to be effective in the treatment of GAD in well-controlled studies.96-98 Hydroxyzine has been widely used in the United States and elsewhere41 for the management of GAD, although some guidelines recommend that this drug should not be used as first-line therapy due to associated side effects (in particular, sedation and anticholinergic effects), slow onset of action, and lack of efficacy for cormorbid disorders.12,34

α2δ ligands. The new generation α2δ ligand pregabalin has consistently shown efficacy in GAD, in addition to its nonpsychiatric uses.99-101 Although the name suggests a GABA-ergic effect, the drug in fact works by modulating presynaptic voltage-sensitive calcium channels, thereby reducing release of glutamate and other neurotransmitters.102-104 Pregabalin is approved in Europe for the treatment of GAD105 and is marketed in the United States for other indications. The drug improves both psychic and somatic symptoms in adults with GAD, including the elderly.105,106 Data also suggest that the efficacy of this agent compares favorably with other anxiolytics: in an effect-size analysis of current treatments for GAD versus placebo, pregabalin was found to have a higher effect size than all of the other pharmacologic modalities in the study (antihistamines, SSRIs, SNRIs, benzodiazepines, azapirones, and herbal or homeopathic medicines).92

The most common side effects associated with pregabalin are somnolence and dizziness.99-101 Weight gain, which is related to dose and duration of exposure, can occur with pregabalin, even after short-term administration.99 Pregabalin is a schedule V controlled substance in the United States, although it is not controlled in Europe, indicating that it has some abuse potential, albeit less than with the benzodiazepines (which are generally schedule IV). Medication discontinuation symptoms have occurred in some patients following abrupt or rapid discontinuation of treatment, indicating that pregabalin should be discontinued by gradual tapering.

Atypical antipsychotics. Some first-generation (“typical”) antipsychotics were approved for a condition similar to GAD, and recent studies have suggested that atypical antipsychotics may also have a role in GAD as defined by current criteria.107,108 Several preliminary reports of monotherapy trials of quetiapine versus placebo have described efficacy at doses in the range of 50-150 mg/d,107,108 but quetiapine cannot yet be recommended as a routine GAD treatment until a full description of efficacy and safety from these studies has been published. However, the use of quetiapine could be considered after other classes of drugs have proved ineffective or when certain types of symptoms are present. While some might advocate olanzapine or risperidone on the basis of published data, these results have been obtained in partial responders to antidepressants rather than as monotherapy in all patients.109,110

Augmentation treatment strategies. In patients who do not respond adequately to initial pharmacologic treatment for GAD, the addition of an atypical antipsychotic agent may provide additional benefit. To date, 3 small, randomized, placebo-controlled augmentation studies have been reported. Low doses of risperidone have been shown to produce improvements in anxiety symptoms when added to existing treatment in patients who had not responded to first-line anxiolytic drugs.58 A study of quetiapine augmentation of paroxetine controlled release, however, did not provide evidence to support the use of quetiapine as an augmenting agent in GAD and found that tolerance of the combination was sometimes problematic, perhaps because both drugs are somewhat sedating or possibly because of CYP 450 isoenzyme interactions.111

Olanzapine has shown augmentation effects in GAD patients who had responded insufficiently to 6 weeks of open-label treatment with fluoxetine. Olanzapine has shown similar augmentation effects when added to fluoxetine in patients with refractory GAD, although this efficacy was achieved at the expense of substantial weight gain.109 Metabolic side effects remain important concerns when atypical antipsychotics are used for GAD; therefore, it is recommended that they be reserved for second-line augmentation treatment. Patients will benefit greatly from more effective and tolerable augmentation agents.

Other augmentation strategies might include addition of a benzodiazepine or other GABAergic drug to an antidepressant. Although we are unaware of any controlled trials in which a benzodiazepine was added to pre-existing antidepressant therapy in GAD,11 it is recommended as a possible strategy. While not an augmentation study in partial responders, there is a single positive study in patients with GAD and marked insomnia in which the nonbenzodiazepine GABA agonist eszopiclone produced a faster and greater response when added to the SSRI antidepressant escitalopram compared with the addition of placebo.112 Augmentation of medication with cognitive-behavioral therapy (CBT) has not been studied meaningfully in GAD, and its benefit still awaits adequate evaluation11; for other anxiety disorders, the evidence of greater gain, relative to single treatment, is mixed, but most studies of this modality have been undertaken in non-treatment-resistant cases.

Pharmacologic Therapies: Long-Term Efficacy

An increasing number of studies show benefit for long-term pharmacotherapy of GAD. Efficacy of venlafaxine extended release (ER) has been demonstrated in two 6-month, placebo-controlled, parallel-group studies of GAD.80,113 The importance of long-term treatment has been demonstrated in a trial with venlafaxine extended release (XR), with increased remission rates at 6 months among patients who had not remitted by week 8.114 In a 24-week, non-placebo-controlled, randomized study comparing the tolerability of escitalopram with paroxetine, the drugs were equally effective, but escitalopram was better tolerated with fewer subjects experiencing adverse events and fewer subjects dropping out early due to adverse events.115

Relapse prevention studies. Two studies have evaluated the role of SNRIs in the prevention of relapse in patients with GAD. The only venlafaxine relapse-prevention study failed to show benefit of maintenance with the drug versus substitution with placebo.116 Duloxetine has been shown to have long-term efficacy among patients with GAD who responded to 26 weeks of open-label treatment; administration of duloxetine for a further 26 weeks reduced the risk of relapse compared with placebo.82

The SSRIs escitalopram (10-20 mg/d) and paroxetine immediate release (20-50 mg/d) have also been shown to be effective in the long-term treatment of GAD.115 Relapse prevention studies have been reported for both drugs.117,118 Escitalopram reduced the risk of relapse compared with placebo during 24 to 72 weeks of randomized treatment following 12 weeks of open-label treatment. Similar results were found with paroxetine versus placebo in a shorter study.

The long-term efficacy of pregabalin has also been demonstrated in patients with GAD. Pregabalin reduced the risk of relapse compared with placebo, during 24 weeks of randomized treatment following 8 weeks of open-label treatment.119 However, differences in study design do not allow for a meaningful comparison of relapse rates between studies.

Psychological therapies. Psychological therapies are an important first-line option in the management of GAD. “Psychoeducation,” including provision of information to patients about the causes and treatment of their condition, has been recommended for all patients.34 This approach also includes paying attention to alcohol, caffeine, and tobacco consumption; regulating sleep; and the control of external stimuli for improving sleep. Simple coping techniques can be taught in the primary care setting for the control of worry, such as setting aside time to rationalize concerns, organizing these into minor and major worries, and identifying priorities and next steps toward addressing them.120 Although data are limited, a review of current research showed that exercise can have a role as an alternative or adjunctive treatment in the management of psychiatric conditions, including anxiety disorders.121

Data strongly support the efficacy of psychosocial treatments for GAD, in particular cognitive therapies and applied relaxation.122,123 A Cochrane collaboration review concluded that current evidence demonstrates that CBT is effective for the short-term management of GAD relative to wait-list control or usual treatment (ie, psychological therapy or pharmacotherapy) but not active supportive therapy or supportive treatment (ie, active supportive therapies underpinned by humanistic principals).124 Either way, the typical controls used in studies of CBT do not approximate to the active treatment as closely as does a placebo tablet to an active drug. However, although CBT is the most effective of the psychological treatments available for GAD, available data indicate that a clinical response occurs in less than 50% of people receiving this form of therapy (46% versus 14% for control), so unmet needs still remain.124

One promising form of psychotherapy emphasizes the promotion of positive emotional states and active coping behaviors, rather than focusing on how to reduce symptoms. This resilience-building treatment is referred to as “well-being therapy” and appears to be superior to CBT on some measures in treatment-resistant GAD and other forms of anxiety.125

Treatment Challenges

Enhancing recognition of GAD. Screening for GAD can potentially be helpful in improving detection rates in primary care, which in turn, can lead to more appropriate treatment and improved patient outcomes. Until recently, there was no validated clinical tool for identifying probable cases of GAD. In view of this unmet need, a 7-item anxiety scale, GAD-7, was developed to facilitate the diagnosis of GAD.126 The GAD-7 scale has been shown to be an efficient tool that can screen for likely cases of GAD and can assess symptom severity and could form an important component of the clinical treatment assessment of GAD.126 Furthermore, another recent study from university-affiliated primary care clinics127 has shown that a 5-question screening questionnaire, the Anxiety and Depression Detector, was a useful screening tool for several anxiety and depressive disorders. Further work needs to be done to determine its usefulness in the primary care setting.

Screening for GAD can be a practical aid to detection and can provide a useful first step within a collaborative or stepwise approach to management. Generally, a positive screen would call for a thorough clinical evaluation on which to base a diagnosis, but it can identify “high-likelihood” cases.127 For such screenings to be useful, it is necessary to have adequate resources for diagnosis and treatment.

Mathias et al128 found that simply reporting the results of positive tests to physicians (who were educated about anxiety and informed of their patients’ condition but did not receive treatment recommendations) and having them monitor progress did not improve physician-reported anxiety symptoms and functional outcome versus patients seen by physicians who did not receive the patient reports.128 Interestingly, patients seen by physicians who received the intervention reported greater improvements in anxiety symptoms and functional status than those who did not.

Recent research indicates that, when patients with GAD did receive psychopharmacologic treatment (ie, SSRIs, SNRIs, TCAs, trazodone) in primary care, it was similar to the type of treatment and doses provided by psychiatrists.30 Overall, these observations support the idea that improved detection of GAD in primary care can help to improve the management of GAD when adequate resources for diagnosis and treatment are available.30

Collaborative care. One innovative form of collaborative care for GAD in the primary care sector is the Coordinated Anxiety Learning and Management (CALM) intervention that has been developed in the United States.129 CALM is currently being evaluated in a prospective, longitudinal, randomized, controlled trial. The intervention has been designed for easy implementation in a variety of primary care settings, and the clinical specialist is involved in the initial patient assessment and patient education.129 The clinical specialist also assists the prescribing physician with medication management and delivering computer-assisted CBT to patients with GAD, as well as panic disorder, posttraumatic stress disorder, social anxiety disorder, and associated comorbidities. Treatment is provided on a stepped-care basis, with additional treatment modalities being added or substituted as necessary. Anxiety symptoms, patient functioning, and satisfaction with care and health care utilization will be assessed at 6-month intervals for 18 months, and the results of this treatment approach are awaited with interest.129

Patient Subgroups

GAD can affect all age groups, including children and the elderly, although few data are available for treatment in these groups.

Elderly. Management of GAD presents challenges in the elderly, owing to the possibility of drug interactions, the high rate of physical comorbidity, and the need for dose adjustment of pharmacotherapy in response to metabolic changes and increased sensitivity to adverse effects.11,130,131 For elderly patients, citalopram has been shown to be effective in the management of late-life anxiety disorders, most of which were GAD, in the first randomized controlled study to evaluate an SSRI for the treatment of GAD in this age group.60 In this study, the most common and troublesome side effect was sedation.

In a post hoc pooled analysis of 4 randomized studies,132 duloxetine was shown to be effective in a subset of elderly patients with GAD but was associated with a high rate of treatment discontinuations due to adverse events. A pooled analysis of 5 randomized, placebo-controlled trials of venlafaxine ER in the treatment of GAD showed that increasing age did not adversely affect response to treatment, with venlafaxine ER demonstrating similar efficacy and tolerability in older subjects (≥ 60 years) compared with younger adults.133

One trial compared CBT, sertraline, and wait-list control in patients with late-life anxiety disorders, of whom only a minority had GAD.134 Patients who received sertraline or CBT experienced significantly greater improvement in anxiety, worry, and depressive symptoms compared with the control group. However, attrition rates were high for both types of intervention, randomization failed, and the intent-to-treat analysis did not match the completer analysis.

A recent 8-week, multicenter, randomized, placebo-controlled trial found that flexibly dosed pregabalin (150-600 mg/d) was effective in improving the symptoms of GAD in this patient population.106

Children and adolescents. For children and adolescents, there are 5 published studies of the treatment of GAD, 3 evaluating the SSRIs sertraline, fluoxetine, and fluvoxamine135-137 and the other 2 evaluating venlafaxine ER.138 These data suggest that these agents may be effective in treating the symptoms of GAD in children and adolescents. The SSRIs are generally well tolerated in this population. Venlafaxine ER, though generally well tolerated over 8 weeks of treatment, was associated with increases in blood pressure and heart rate and a decrease in weight, as well as a lesser increase in height relative to placebo.137 These effects of venlafaxine ER could become clinically significant safety concerns during long-term treatment.

Guidelines from the British Association for Psychopharmacology recommend that, in children, pharmacologic treatments should be reserved for individuals who have not responded to psychological therapies. However, it seems reasonable to consider using drugs for which there is good evidence of benefit in children with GAD, even though they may not carry an official indication, after carefully weighing the benefits and risks in individual cases. Careful consideration of dosage is also necessary when prescribing for children, along with monitoring for adverse effects, bearing in mind that young people might have difficulty describing these effects.38 In addition, the risk of possible suicidal thoughts or behaviors should be considered and these potential adverse effects monitored when any antidepressants are administered in this age group.73

Treatment resistance. Patients with treatment-resistant GAD present a particular challenge. When initial treatments fail, switching to another evidence-based treatment is recommended.38 For patients who prove to be refractory to treatment, referral to specialist mental health services is recommended.38,41

Adherence and Patient Education

Achieving a satisfactory treatment response and reducing the risk of relapse depends, in part, on adherence to therapy. While data to our knowledge have not been reported separately for GAD, nonadherence to antidepressant medication at 6 months in patients with anxiety disorders has been reported to be 53%-70% in 2 separate studies of managed care populations.138,139 These rates are similar to 6-month nonadherence rates in major depressive disorder.140,141 Possible reasons include lack of efficacy, delay in treatment effect, side effects, and improvement of symptoms (so patients feel they no longer need treatment). One study of patients with GAD or panic disorder found that personality traits involving novelty seeking predicted early discontinuation from clinical trials.142

Ambivalence about treatment and perceived stigma associated with receiving treatment for a psychiatric condition are also important factors that can reduce adherence to therapy.141 For example, in major depressive disorder, compliance with antidepressant therapy has been shown to be influenced by the views of individual patients, with perceived stigma having an important negative influence on treatment adherence.143 Research on antidepressant use in major depression has found that adherence can be improved by increasing clinician awareness about the extent of nonadherence, better understanding about stigma and other patient concerns, patient education, and strengthening the therapeutic alliance.141 We believe these same approaches could profitably be used for GAD.

GAD is usually chronic with a waxing and waning course, and continued support and education is often required. Patients should be given clear information on how long treatment will take to become effective and how to cope with their symptoms in the meantime. Psychological and antidepressant therapies do not generally produce as rapid a response compared to benzodiazepines, antipsychotics, and α2δ ligands. Patients should be advised that speed (and type) of initial response varies according to drug but that marked improvement may require several weeks of treatment12 and remission even longer.113 Patients also need to know how long to expect to remain on treatment and how to deal with any side effects that might arise. Given the chronic nature of GAD, long-term treatment of at least 12 months is usually recommended.12,38

CONCLUSIONS

GAD is the most frequent anxiety disorder seen in primary care. In view of its chronic and disabling nature, additional efforts are needed to recognize and diagnose the disorder and to use evidence-based effective treatments. Effective management of GAD has the potential to improve quality of life for patients and their families, as well as improve patient productivity and reduce the impact of the condition on health care resources. We believe that the use of appropriate screening tools and providing information to patients with GAD on their condition and its treatment are an important starting point toward increasing recognition and appropriate treatment of GAD.

The evidence base for GAD has grown in recent years, although many questions remain unanswered regarding the optimization of treatment for the individual patient. Most interventions have similar overall benefit, and much of the evidence to support their therapeutic value comes from studies of single treatments rather than the combinations, which are often needed for more complex cases. Here, the data are lacking. More research is needed into the treatment of comorbid and treatment-resistant forms of GAD, the impact of particular symptoms on choice of treatment, and the efficacy of treatments in patient subgroups such as children and the elderly. An additional question concerns the advisability of commencing at low doses with a progressive build-up versus beginning at a moderate dose. To some extent, this might be determined by the clinical history (eg, sensitivity to side effects of drugs), attitude toward drugs (eg, ambivalence and reluctance to tolerate untoward experiences), salient symptoms (eg, panic type and autonomic instability), and general anxiety sensitivity; to date, there is an absence of good empirical data in GAD.

At present, a need exists for the development of novel approaches for treating GAD. These include the development and dissemination of more easily adopted forms of psychotherapy, eg, self-directed therapy and briefer forms of treatment. With respect to drug therapies, the optimal properties would be a drug that is well tolerated, fast acting, beneficial on sleep, effective across a range of related disorders, and devoid of withdrawal symptoms and adverse interactions with other medications.

Drug names: buspirone (BuSpar and others), citalopram (Celexa, Lexapro, and others), duloxetine (Cymbalta), escitalopram (Lexapro and others), eszopiclone (Lunesta), fluoxetine (Prozac, Sarafem, and others), fluvoxamine (Luvox and others), hydroxyzine (Vistaril and others), imipramine (Tofranil and others), olanzapine (Zyprexa), paroxetine (Paxil, Pexeva, and others), pregabalin (Lyrica), quetiapine (Seroquel), risperidone (Risperdal and others), sertraline (Zoloft and others), tiagabine (Gabitril), venlafaxine (Effexor and others).

Author affiliations: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina (Dr Davidson); Pfizer Global Research and Development, New London, Connecticut (Dr Feltner); and Pfizer Inc Worldwide Pharmaceutical Operations, Global Medical, New York, New York (Dr Dugar).

Potential conflicts of interest: Dr Davidson has served as a speaker and received honoraria from AMBAT (Sao Paulo, Brazil), American Psychiatric Association, DCH Regional Medical Center (Tuscaloosa, Alabama), GlaxoSmithKline CME Institute, Madison Institute of Medicine, Sharp Health Care Inc, University of Pennsylvania, and University of Southern California; has served as an advisor to AstraZeneca, GlaxoSmithKline, Jazz, Pfizer, Sepracor, Shire, Transcept, ZARS; has received royalties for the Davidson Trauma Scale, from American Psychiatric Association, Guilford Publications, and MultiHealth Systems Inc; and has received licence fees for the Connor-Davidson Resilience Scale and Social Phobia Inventory. Drs Feltner and Dugar are employees of Pfizer Inc and hold stock ownership in that company.

Funding/support: None reported.

Acknowledgment: Editorial support was provided by Jennifer Edwards, MB, BS, a medical writer at Gardiner-Caldwell Communications, Berkshire, England, and was funded by Pfizer Inc.

REFERENCES

1. Wittchen HU. Generalized anxiety disorder: prevalence, burden, and cost to society. Depress Anxiety. 2002;16(4):162-171. PubMed doi:10.1002/da.10065

2. Wittchen HU, Kessler RC, Beesdo K, et al. Generalized anxiety and depression in primary care: prevalence, recognition, and management. J Clin Psychiatry. 2002;63(suppl 8):24-34. PubMed

3. Wittchen HU, Hoyer J. Generalized anxiety disorder: nature and course. J Clin Psychiatry. 2001;62(suppl 11):15-19. PubMed

4. לst׼n TB, Sartorius N. Mental Illness in General Health Care: An International Study. Chichester, United Kingdom: Wiley; 1995:323-335.

5. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):593-602. PubMed doi:10.1001/archpsyc.62.6.593

6. Alonso J, Angermeyer MC, Bernert S, et al. Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr Scand Suppl. 2004;(420):21-27. PubMed

7. Kessler RC. The global burden of anxiety and mood disorders: putting the European Study of the Epidemiology of Mental Disorders (ESEMeD) findings into perspective. J Clin Psychiatry. 2007;68(suppl 2):10-19. PubMed

8. Beekman AT, Bremmer MA, Deeg DJ, et al. Anxiety disorders in later life: a report from the Longitudinal Aging Study Amsterdam. Int J Geriatr Psychiatry. 1998;13(10):717-726. PubMed doi:10.1002/(SICI)1099-1166(1998100)13:10<717::AID-GPS857>3.0.CO;2-M

9. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Press; 1994:432-436.

10. World Health Organization. Tenth Revision of the International Classification of Diseases. Geneva, Switzerland: World Health Organization; 1991:Section V:F41.1.

11. Davidson J, Zhang W, Connor K, et al. A psychopharmacological treatment algorithm for generalised anxiety disorder (GAD). J Psychopharmacol. 2010;24(1):3-26. PubMed

12. International Psychopharmacology Algorithm Project. IPAP General Anxiety Disorder (GAD) Algorithm Notes. http://www.ipap.org/gad/index.php. Accessed November 2008.

13. Ruscio AM, Chiu WT, Roy-Byrne P, et al. Broadening the definition of generalized anxiety disorder: effects on prevalence and associations with other disorders in the National Comorbidity Survey Replication. J Anxiety Disord. 2007;21(5):662-676. PubMed doi:10.1016/j.janxdis.2006.10.004

14. Tonks A. Treating generalised anxiety disorder. BMJ. 2003;326(7391):700-702. PubMed doi:10.1136/bmj.326.7391.700

15. Rodriguez BF, Weisberg RB, Pagano ME, et al. Characteristics and predictors of full and partial recovery from generalized anxiety disorder in primary care patients. J Nerv Ment Dis. 2006;194(2):91-97. PubMed doi:10.1097/01.nmd.0000198140.02154.32

16. Massion AO, Warshaw MG, Keller MB. Quality of life and psychiatric morbidity in panic disorder and generalized anxiety disorder. Am J Psychiatry. 1993;150(4):600-607. PubMed

17. Kessler RC. The epidemiology of pure and comorbid generalized anxiety disorder: a review and evaluation of recent research. Acta Psychiatr Scand Suppl. 2000;(406):7-13. PubMed doi:10.1111/j.0065-1591.2000.acp29[dash]02.x

18. Alonso J, Angermeyer MC, Bernert S, et al. 12-month comorbidity patterns and associated factors in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr Scand Suppl. 2004;(420):28-37. PubMed

19. Wittchen HU, Zhao S, Kessler RC, et al. DSM-III-R generalized anxiety disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51(5):355-364. PubMed

20. Lieb R, Meinlschmidt G, Araya R. Epidemiology of the association between somatoform disorders and anxiety and depressive disorders: an update. Psychosom Med. 2007;69(9):860-863. PubMed doi:10.1097/PSY.0b013e31815b0103

21. Roy-Byrne PP, Katon W. Generalized anxiety disorder in primary care: the precursor/modifier pathway to increased health care utilization. J Clin Psychiatry. 1997;58(suppl 3):34-38, 39-40. PubMed

22. Conway KP, Compton W, Stinson FS, et al. Lifetime comorbidity of DSM-IV mood and anxiety disorders and specific drug use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2006;67(2)247-257. PubMed

23. Rodriguez BF, Weisberg RB, Pagano ME, et al. Frequency and patterns of psychiatric comorbidity in a sample of primary care patients with anxiety disorders. Compr Psychiatry. 2004;45(2):129-137. PubMed doi:10.1016/j.comppsych.2003.09.005

24. Harter MC, Conway KP, Merikangas KR. Associations between anxiety disorders and physical illness. Eur Arch Psychiatry Clin Neurosci. 2003;253(6):313-320. PubMed doi:10.1007/s00406-003-0449-y

25. Bowen RC, Senthilselvan A, Barale A. Physical illness as an outcome of chronic anxiety disorders. Can J Psychiatry. 2000;45(5):459-464. PubMed

26. McWilliams LA, Cox BJ, Enns MW. Mood and anxiety disorders associated with chronic pain: an examination in a nationally representative sample. Pain. 2003;106(1-2):127-133. PubMed doi:10.1016/S0304-3959(03)00301-4

27. Roy-Byrne PP, Davidson KW, Kessler RC, et al. Anxiety disorders and comorbid medical illness. Gen Hosp Psychiatry. 2008;30(3):208-225. PubMed doi:10.1016/j.genhosppsych.2007.12.006

28. Nutt D, Argyropoulos S, Hood S, et al. Generalized anxiety disorder: a comorbid disease. Eur Neuropsychopharmacol. 2006;16(suppl 2):S109-S118. PubMed doi:10.1016/j.euroneuro.2006.04.003

29. Maki KM, Weisberg RB, Dyck I, et al. The impact of comorbid pain disorders on the symptomatic course and functioning of primary care patients with anxiety disorders. Presented at the 27th Annual Conference of the Anxiety Disorders Association of America; March 6-9, 2008; St Louis, MO

30. Weisberg RB, Dyck I, Culpepper L, et al. Psychiatric treatment in primary care patients with anxiety disorders: a comparison of care received from primary care providers and psychiatrists. Am J Psychiatry. 2007;164(2):276-282. PubMed doi:10.1176/appi.ajp.164.2.276

31. Kessler D, Lloyd K, Lewis G, et al. Cross sectional study of symptom attribution and recognition of depression and anxiety in primary care. BMJ. 1999;318(7181)436-439. PubMed

32. Kessler RC, Mickelson KD, Barber C, et al. The association between chronic medical disorders and work impairment. In: Rossi AS, ed. Caring and Doing For Others: Social Responsibility in the Domains of Family, Work and Community. Chicago, IL: University of Chicago Press; 2001:403-426.

33. Kessler RC, Greenberg PE. The economic burden of anxiety and stress disorders. In: Davis KL, Charney D, Coyle JT, et al, eds. Neuropsychopharmacology: The Fifth Generation of Progress. Baltimore, MD: Lippincott Williams and Wilkins; 2002:981-992.

34. Bandelow B, Zohar J, Hollander E, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders: First Revision. World J Biol Psychiatry. 2008;9(4):248-312. PubMed doi:10.1080/15622970802465807

35. Goodwin RD, Gorman JM. Psychopharmacologic treatment of generalized anxiety disorder and the risk of major depression. Am J Psychiatry. 2002;159(11):1935-1937. PubMed doi:10.1176/appi.ajp.159.11.1935

36. Altamura AC, Dell’ osso B, D’ Urso N, et al. Duration of untreated illness as a predictor of treatment response and clinical course in generalized anxiety disorder. CNS Spectr. 2008;13(5):415-422. PubMed

37. Allgulander C, Hirschfeld RM, Nutt DJ. Long-term treatment strategies in anxiety disorders. Psychopharmacol Bull. 2002;36(suppl 2):79-92. PubMed

38. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2005;19(6):567-596. PubMed doi:10.1177/0269881105059253

39. Swinson RP, Anthony MM, Bleau P, et al. Clinical practice guidelines: management of anxiety disorders. Can J Psychiatry. 2006;51(suppl 2):9S-91S. PubMed

40. Ballenger JC, Davidson JR, Lecrubier Y, et al. Consensus statement on generalized anxiety disorder from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry. 2001;62(suppl 11):53-58. PubMed

41. The National Institute of Clinical Excellence (NICE). Management of anxiety (panic disorder, with or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary and community care; April 2007. http://www.nice.org.uk/nicemedia/pdf/CG022NICEguidelineamended.pdf. Accessed November 2008.

42. Shader RI, Greenblatt DJ. Use of benzodiazepines in anxiety disorders. N Engl J Med. 1993;328(19):1398-1405. PubMed doi:10.1056/NEJM199305133281907

43. Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):617-627. PubMed doi:10.1001/archpsyc.62.6.617

44. Moroz G. High-potency benzodiazepines: recent clinical results. J Clin Psychiatry. 2004;65(suppl 5):13-18. PubMed

45. Hidalgo RB, Barnett SD, Davidson JR. Social anxiety disorder in review: two decades of progress. Int J Neuropsychopharmacol. 2001;4(3):279-298. PubMed doi:10.1017/S1461145701002504

46. Curry DT, Eisenstein RD, Walsh JK. Pharmacologic management of insomnia: past, present, and future. Psychiatr Clin North Am. 2006;29(4):871-893. PubMed doi:10.1016/j.psc.2006.09.006

47. Petrovic M, Mariman A, Warie H, et al. Is there a rationale for prescription of benzodiazepines in the elderly? review of the literature. Acta Clin Belg. 2003;58(1):27-36. PubMed

48. Longo LP, Johnson B. Addiction, pt 1: benzodiazepines: side effects, abuse risk and alternatives. Am Fam Physician. 2000;61(7):2121-2128. PubMed

49. Schweizer E, Rickels K. Benzodiazepine dependence and withdrawal: a review of the syndrome and its clinical management. Acta Psychiatr Scand Suppl. 1998;98(s393):95-101. doi:10.1111/j.1600-0447.1998.tb05973.x

50. Lader M. Anxiolytic drugs: dependence, addiction and abuse. Eur Neuropsychopharmacol. 1994;4(2):85-91. PubMed doi:10.1016/0924-977X(94)90001-9

51. Schatzberg AF, Nemeroff CB. Textbook of Psychopharmacology, 2nd ed. Washington, DC: American Psychiatric Press; 1998:279-280, 360-361, 969.

52. Fraser AD. Use and abuse of the benzodiazepines. Ther Drug Monit. 1998;20(5):481-489. PubMed doi:10.1097/00007691-199810000-00007

53. Pollack MH, Tiller J, Xie F, et al. Tiagabine in adult patients with generalized anxiety disorder: results from 3 randomized, double-blind, placebo-controlled, parallel-group studies. J Clin Psychopharmacol. 2008;28(3):308-316. PubMed doi:10.1097/JCP.0b013e318172b45f

54. Kapczinski F, Lima MS, Souza JS, et al. Antidepressants for generalized anxiety disorder. Cochrane Database Syst Rev. 2003;(2):CD003592. PubMed

55. GlaxoSmithKline. Seroxat [summary of product characteristics]. Middlesex, UK: GlaxoSmithKline; June 9, 2008. http://emc.medicines.org.uk/emc/assets/c/html/DisplayDoc.asp?DocumentID=2057.

56. Einarson A, Pistelli A, DeSantis M, et al. Evaluation of the risk of congenital cardiovascular defects associated with use of paroxetine during pregnancy. Am J Psychiatry. 2008;165(6):749-752. PubMed doi:10.1176/appi.ajp.2007.07060879

57. Allgulander C, Dahl AA, Austin C, et al. Efficacy of sertraline in a 12-week trial for generalized anxiety disorder. Am J Psychiatry. 2004;161(9):1642-1649. PubMed doi:10.1176/appi.ajp.161.9.1642

58. Brawman-Mintzer O, Knapp RG, Rynn M, et al. Sertraline treatment for generalized anxiety disorder: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2006;67(6):874-881. PubMed

59. Dahl AA, Ravindran A, Allgulander C, et al. Sertraline in generalized anxiety disorder: efficacy in treating the psychic and somatic anxiety factors. Acta Psychiatr Scand. 2005;111(6):429-435. PubMed doi:10.1111/j.1600-0447.2005.00529.x

60. Lenze EJ, Mulsant BH, Shear MK, et al. Efficacy and tolerability of citalopram in the treatment of late-life anxiety disorders: results from an 8-week randomized, placebo-controlled trial. Am J Psychiatry. 2005;162(1):146-150. PubMed doi:10.1176/appi.ajp.162.1.146

61. Brambilla P, Cipriani A, Hotopf M, et al. Side effect profile of fluoxetine in comparison with other SSRIs, tricyclic and newer antidepressants: a meta-analysis of clinical trial data. Pharmacopsychiatry. 2005;38(2):69-77. PubMed doi:10.1055/s-2005-837806

62. Spigset O. Adverse reactions of selective serotonin reuptake inhibitors: reports from a spontaneous reporting system. Drug Saf. 1999;20(3):277-287. PubMed doi:10.2165/00002018-199920030-00007

63. Hirschfeld RM. Long-term side effects of SSRIs: sexual dysfunction and weight gain. J Clin Psychiatry. 2003;64(suppl 18):20-24. PubMed

64. Hu XH, Bull SA, Hunkeler EM, et al. Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate. J Clin Psychiatry. 2004;65(7):959-965. PubMed

65. Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry. 2002;63(4):357-366. PubMed

66. Clayton A, Keller A, McGarvey EL. Burden of phase-specific sexual dysfunction with SSRIs. J Affect Disord. 2006;91(1):27-32. PubMed doi:10.1016/j.jad.2005.12.007

67. Movig KL, Janssen MW, de Waal MJ, et al. Relationship of serotonergic antidepressants and need for blood transfusion in orthopedic surgical patients. Arch Intern Med. 2003;163(19):2354-2358. PubMed doi:10.1001/archinte.163.19.2354

68. Williams LJ, Henry MJ, Berk M, et al. Selective serotonin reuptake inhibitor use and bone mineral density in women with a history of depression. Int Clin Psychopharmacol. 2008;23(2):84-87. PubMed doi:10.1097/YIC.0b013e3282f2b3bb

69. Fabian TJ, Amico JA, Kroboth PD, et al. Paroxetine-induced hyponatremia in older adults: a 12-week prospective study. Arch Intern Med. 2004;164(3):327-332. PubMed doi:10.1001/archinte.164.3.327

70. Ashton AK, Jamerson BD, Weinstein WL, et al. Antidepressant-related adverse effects impacting treatment compliance: results of a patient survey. Curr Ther Res. 2005;66(2):96-106. doi:10.1016/j.curtheres.2005.04.006

71. Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998;44(2):77-87. PubMed doi:10.1016/S0006-3223(98)00126-7

72. Fergusson D, Doucette S, Glass KC, et al. Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials. BMJ. 2005;330(7488):396. PubMed doi:10.1136/bmj.330.7488.396

73. US Food and Drug Administration. Revisions to product labeling: suicidality and antidepressant drugs; 2007. http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/UCM096273. Accessed November 2008.

74. US Food and Drug Administration. Review and evaluation of clinical data: relationship between psychotropic drugs and pediatric suicidality; August 16, 2004. http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-10-TAB08-Hammads-Review.pdf. Accessed November 2008.

75. US Food and Drug Administration. Clinical review: relationship between antidepressant drugs and suicidality in adults; November 16, 2006. http://www.fda.gov/OHRMS/DOCKETS/AC/06/briefing/2006-4272b1-01-FDA.pdf. Accessed November 2008.

76. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006;63(3):332-339. PubMed doi:10.1001/archpsyc.63.3.332

77. Leon AC. The revised black box warning for antidepressants sets a public health experiment in motion. J Clin Psychiatry. 2007;68(7):1139-1141. PubMed

78. Gibbons RD, Hur K, Bhaumik DK, et al. The relationship between antidepressant prescription rates and rate of early adolescent suicide. Am J Psychiatry. 2006;163(11):1898-1904. PubMed doi:10.1176/appi.ajp.163.11.1898

79. Gibbons RD, Brown CH, Hur K, et al. Relationship between antidepressants and suicide attempts: an analysis of the Veterans Health Administration data sets. Am J Psychiatry. 2007;164(7):1044-1049. PubMed doi:10.1176/appi.ajp.164.7.1044

80. Allgulander C, Hackett D, Salinas E. Venlafaxine extended release (ER) in the treatment of generalised anxiety disorder: 24-week placebo-controlled dose-ranging study. Br J Psychiatry. 2001;179:15-22. PubMed doi:10.1192/bjp.179.1.15

81. Ballenger JC. Overview of different pharmacotherapies for attaining remission in generalized anxiety disorder. J Clin Psychiatry. 2001;62:11-19. PubMed

82. Davidson JR, Wittchen HU, Llorca PM, et al. Duloxetine treatment for relapse prevention in adults with generalized anxiety disorder: a double-blind placebo-controlled trial. Eur Neuropsychopharmacol. 2008;18(9):673-681. PubMed doi:10.1016/j.euroneuro.2008.05.002

83. Rynn MA, Riddle MA, Yeung PP, et al. Efficacy and safety of extended-release venlafaxine in the treatment of generalized anxiety disorder in children and adolescents: two placebo-controlled trials. Am J Psychiatry. 2007;164(2):290-300. PubMed doi:10.1176/appi.ajp.164.2.290

84. Sheehan DV. Attaining remission in generalized anxiety disorder: venlafaxine extended release comparative data. J Clin Psychiatry. 2001;62(supp 19):26-31. PubMed

85. Thase ME. Effects of venlafaxine on blood pressure: a meta-analysis of original data from 3744 depressed patients. J Clin Psychiatry. 1998;59(10):502-508. PubMed

86. Campagne DM. Venlafaxine and serious withdrawal symptoms: warning to drivers. MedGenMed. 2005;7(3):22. PubMed

87. Perahia DG, Kajdasz DK, Desaiah D, et al. Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder. J Affect Disord. 2005;89(1-3):207-212. PubMed doi:10.1016/j.jad.2005.09.003

88. Wyeth Pharmaceuticals Inc. Effexor XR [prescribing information]. Philadelphia, IN: Wyeth Pharmaceuticals Inc. http://www.wyeth.com/content/showlabeling.asp?id=100. Accessed December 2008.

89. Eli Lilly and Company. Cymbalta [prescribing information]. Indianapolis, IN: Eli Lilly and Company. http://pi.lilly.com/us/cymbalta-pi.pdf. Accessed December 2008.

90. Rickels K, Downing R, Schweizer E, et al. Antidepressants for the treatment of generalized anxiety disorder: a placebo-controlled comparison of imipramine, trazodone, and diazepam. Arch Gen Psychiatry. 1993;50(11):884-895. PubMed

91. Goa KL, Ward A. Buspirone: a preliminary review of its pharmacological properties and therapeutic efficacy as an anxiolytic. Drugs. 1986;32(2):114-129. PubMed doi:10.2165/00003495-198632020-00002

92. Hidalgo RB, Tupler LA, Davidson JR. An effect-size analysis of pharmacologic treatments for generalized anxiety disorder. J Psychopharmacol. 2007;21(8):864-872. PubMed doi:10.1177/0269881107076996

93. Laakmann G, Schule C, Lorkowski G, et al. Buspirone and lorazepam in the treatment of generalized anxiety disorder in outpatients. Psychopharmacology (Berl). 1998;136(4):357-366. PubMed doi:10.1007/s002130050578

94. Olajide D, Lader M. A comparison of buspirone, diazepam, and placebo in patients with chronic anxiety states. J Clin Psychopharmacol. 1987;7(3):148-152. PubMed doi:10.1097/00004714-198706000-00005

95. Chessick CA, Allen MH, Thase M, et al. Azapirones for generalized anxiety disorder. Cochrane Database Syst Rev. 2006;3:CD006115. PubMed

96. Lader M, Scotto JC. A multicentre double-blind comparison of hydroxyzine, buspirone and placebo in patients with generalized anxiety disorder. Psychopharmacology (Berl). 1998;139 (4):402-406. PubMed doi:10.1007/s002130050731

97. Darcis T, Ferreri M, Natens J, et al. A multicentre double-blind placebo-controlled study investigating the anxiolytic efficacy of hydroxyzine in patients with generalized anxiety. Hum Psychopharmacol. 1995;10(3):181-187. doi:10.1002/hup.470100303

98. Llorca PM, Spadone C, Sol O, et al. Efficacy and safety of hydroxyzine in the treatment of generalized anxiety disorder: a 3-month double-blind study. J Clin Psychiatry. 2002;63(11):1020-1027. PubMed

99. Pande AC, Crockatt JG, Feltner DE, et al. Pregabalin in generalized anxiety disorder: a placebo-controlled trial. Am J Psychiatry. 2003;160(3):533-540. PubMed doi:10.1176/appi.ajp.160.3.533

100. Pohl RB, Feltner DE, Fieve RR, et al. Efficacy of pregabalin in the treatment of generalized anxiety disorder: double-blind, placebo-controlled comparison of BID versus TID dosing. J Clin Psychopharmacol. 2005;25(2):151-158. PubMed doi:10.1097/01.jcp.0000155820.74832.b0

101. Rickels K, Pollack MH, Feltner DE, et al. Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam. Arch Gen Psychiatry. 2005;62(9):1022-1030. PubMed doi:10.1001/archpsyc.62.9.1022

102. Dooley DJ, Taylor CP, Donevan S, et al. Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission. Trends Pharmacol Sci. 2007;28(2):75-82. PubMed doi:10.1016/j.tips.2006.12.006

103. Kavoussi R. Pregabalin: from molecule to medicine. Eur Neuropsychopharmacol. 2006;16(suppl 2):S128-S133. PubMed doi:10.1016/j.euroneuro.2006.04.005

104. Stahl SM. Anticonvulsants as anxiolytics, part 2: pregabalin and gabapentin as alpha(2)delta ligands at voltage-gated calcium channels. J Clin Psychiatry. 2004;65(4):460-461. PubMed

105. Montgomery SA. Pregabalin for the treatment of generalised anxiety disorder. Expert Opin Pharmacother. 2006;7(15):2139-2154. PubMed doi:10.1517/14656566.7.15.2139

106. Montgomery S, Chatamra K, Pauer L, et al. Efficacy and safety of pregabalin in elderly people with generalised anxiety disorder. Br J Psychiatry. 2008;193(5):389-394. PubMed doi:10.1192/bjp.bp.107.037788

107. Chouinard G, Ahokas A, Bandelow B, et al. Extended release quetiapine fumarate (quetiapine XR) once-daily monotherapy in generalized anxiety disorder (GAD). Presented at the 27th Annual Meeting of the Anxiety Disorders Association of America; March 6-9, 2008; St Louis, MO.

108. Khan A, Joyce M, Eggens I, et al. Extended release quetiapine fumarate (quetiapine XR) monotherapy in the treatment of generalized anxiety disorder (GAD). Presented at the 27th Annual Meeting of the Anxiety Disorders Association of America; March 6-9, 2008; St Louis, MO.

109. Pollack MH, Simon NM, Zalta AK, et al. Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo-controlled study. Biol Psychiatry. 2006;59(3):211-215. PubMed doi:10.1016/j.biopsych.2005.07.005

110. Brawman-Mintzer O, Knapp RG, Nietert PJ. Adjunctive risperidone in generalized anxiety disorder: a double-blind, placebo-controlled study. J Clin Psychiatry. 2005;66(10):1321-1325. PubMed

111. Simon NM, Connor KM, LeBeau RT, et al. Quetiapine augmentation of paroxetine CR for the treatment of refractory generalized anxiety disorder: preliminary findings. Psychopharmacology (Berl). 2008;197(4):675-681. PubMed doi:10.1007/s00213-008-1087-x

112. Pollack M, Kinrys G, Krystal A, et al. Eszopiclone coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder. Arch Gen Psychiatry. 2008;65(5):551-562. PubMed doi:10.1001/archpsyc.65.5.551

113. Gelenberg AJ, Lydiard RB, Rudolph RL, et al. Efficacy of venlafaxine extended-release capsules in nondepressed outpatients with generalized anxiety disorder: a 6-month randomized controlled trial. JAMA. 2000;283(23):3082-3088. PubMed doi:10.1001/jama.283.23.3082

114. Montgomery SA, Sheehan DV, Meoni P, et al. Characterization of the longitudinal course of improvement in generalized anxiety disorder during long-term treatment with venlafaxine XR. J Psychiatr Res. 2002;36(4):209-217. PubMed doi:10.1016/S0022-3956(02)00005-5

115. Bielski RJ, Bose A, Chang CC. A double-blind comparison of escitalopram and paroxetine in the long-term treatment of generalized anxiety disorder. Ann Clin Psychiatry. 2005;17(2):65-69. PubMed doi:10.1080/10401230590932326

116. Hackett D, White C, Salinas E. Relapse prevention in patients with generalized anxiety disorder (GAD) by treatment with venlafaxine ER. Presented at the 1st International Forum on Mood and Anxiety Disorders; November 29-December 2, 2000; Monte Carlo, Monaco.

117. Allgulander C, Florea I, Huusom AK. Prevention of relapse in generalized anxiety disorder by escitalopram treatment. Int J Neuropsychopharmacol. 2006;9(5):495-505. PubMed doi:10.1017/S1461145705005973

118. Stocchi F, Nordera G, Jokinen RH, et al. Efficacy and tolerability of paroxetine for the long-term treatment of generalized anxiety disorder. J Clin Psychiatry. 2003;64(3):250-258. PubMed

119. Feltner D, Wittchen HU, Kavoussi R, et al. Long-term efficacy of pregabalin in generalized anxiety disorder. Int Clin Psychopharmacol. 2008;23(1):18-28. PubMed doi:10.1097/YIC.0b013e3282f0f0d7

120. Culpepper L. Generalized anxiety disorder in primary care: emerging issues in management and treatment. J Clin Psychiatry. 2002;63(suppl 8):35-42. PubMed

121. Barbour KA, Edenfield TM, Blumenthal JA. Exercise as a treatment for depression and other psychiatric disorders: a review. J Cardiopulm Rehabil Prev. 2007;27(6):359-367. PubMed

122. Borkovec TD, Ruscio AM. Psychotherapy for generalized anxiety disorder. J Clin Psychiatry. 2001;62(suppl 11):37-42. PubMed

123. Ost LG, Breitholtz E. Applied relaxation vs cognitive therapy in the treatment of generalized anxiety disorder. Behav Res Ther. 2000;38(8):777-790. PubMed doi:10.1016/S0005-7967(99)00095-9

124. Hunot V, Churchill R, Silva de Lima M, et al. Psychological therapies for generalised anxiety disorder. Cochrane Database Syst Rev. 2007;(1):CD001848. PubMed

125. Fava GA, Ruini C, Rafanelli C, et al. Well-being therapy of generalized anxiety disorder. Psychother Psychosom. 2005;74(1):26-30. PubMed doi:10.1159/000082023

126. Spitzer RL, Kroenke K, Williams JB, et al. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092-1097. PubMed doi:10.1001/archinte.166.10.1092

127. Means-Christensen AJ, Sherbourne CD, Roy-Byrne PP, et al. Using five questions to screen for five common mental disorders in primary care: diagnostic accuracy of the Anxiety and Depression Detector. Gen Hosp Psychiatry. 2006;28(2):108-118. PubMed doi:10.1016/j.genhosppsych.2005.08.010

128. Mathias SD, Fifer SK, Mazonson PD, et al. Necessary but not sufficient: the effect of screening and feedback on outcomes of primary care patients with untreated anxiety. J Gen Intern Med. 1994;9(11):606-615. PubMed doi:10.1007/BF02600303

129. Sullivan G, Craske MG, Sherbourne C, et al. Design of the Coordinated Anxiety Learning and Management (CALM) study: innovations in collaborative care for anxiety disorders. Gen Hosp Psychiatry. 2007;29(5):379-387. PubMed doi:10.1016/j.genhosppsych.2007.04.005

130. Jacob S, Spinler SA. Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults. Ann Pharmacother. 2006;40(9):1618-1622. PubMed doi:10.1345/aph.1G293

131. Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol. 2003;38(8):843-853. PubMed doi:10.1016/S0531-5565(03)00133-5

132. Davidson J, Allgulander C, Pollack MH, et al. Efficacy and tolerability of duloxetine in elderly patients with generalized anxiety disorder: a pooled analysis of four randomized, double-blind, placebo-controlled studies. Hum Psychopharmacol. 2008;23(6):519-526. PubMed doi:10.1002/hup.949

133. Katz IR, Reynolds CF 3rd, Alexopoulos GS, et al. Venlafaxine ER as a treatment for generalized anxiety disorder in older adults: pooled analysis of five randomized placebo-controlled clinical trials. J Am Geriatr Soc. 2002;50(1):18-25. PubMed doi:10.1046/j.1532-5415.2002.50003.x

134. Schuurmans J, Comijs H, Emmelkamp PM, et al. A randomized, controlled trial of the effectiveness of cognitive-behavioral therapy and sertraline versus a waitlist control group for anxiety disorders in older adults. Am J Geriatr Psychiatry. 2006;14(3):255-263. PubMed doi:10.1097/01.JGP.0000196629.19634.00

135. Walkup JT, Labellarte MJ, Riddle MA, et al, for the Research Unit on Pediatric Psychopharmacology Anxiety Study Group. Fluvoxamine for the treatment of anxiety disorders in children and adolescents. N Engl J Med. 2001;344(17):1279-1285. PubMed doi:10.1056/NEJM200104263441703

136. Birmaher B, Axelson DA, Monk K, et al. Fluoxetine for the treatment of childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2003;42(4):415-423. PubMed

137. Rynn MA, Siqueland L, Rickels K. Placebo-controlled trial of sertraline in the treatment of children with generalized anxiety disorder. Am J Psychiatry. 2001;158(12):2008-2014. PubMed doi:10.1176/appi.ajp.158.12.2008

138. Sheehan DV, Keene MS, Eaddy M, et al. Differences in medication adherence and healthcare resource utilization patterns: older versus newer antidepressant agents in patients with depression and/or anxiety disorders. CNS Drugs. 2008;22(11):963-973. PubMed doi:10.2165/00023210-200822110-00005

139. Stein MB, Cantrell CR, Sokol MC, et al. Antidepressant adherence and medical resource use among managed care patients with anxiety disorders. Psychiatr Serv. 2006;57(5):673-680. PubMed doi:10.1176/appi.ps.57.5.673

140. Lin EH, Von KM, Katon W, et al. The role of the primary care physician in patients’ adherence to antidepressant therapy. Med Care. 1995;33(1):67-74. PubMed doi:10.1097/00005650-199501000-00006

141. Lin EH, Von KM, Ludman EJ, et al. Enhancing adherence to prevent depression relapse in primary care. Gen Hosp Psychiatry. 2003;25(5):303-310. PubMed doi:10.1016/S0163-8343(03)00074-4

142. Wingerson D, Sullivan M, Dager S, et al. Personality traits and early discontinuation from clinical trials in anxious patients. J Clin Psychopharmacol. 1993;13(3):194-197. PubMed doi:10.1097/00004714-199306000-00007

143. Sirey JA, Bruce ML, Alexopoulos GS, et al. Stigma as a barrier to recovery: perceived stigma and patient-rated severity of illness as predictors of antidepressant drug adherence. Psychiatr Serv. 2001;52(12):1615-1620. PubMed doi:10.1176/appi.ps.52.12.1615