Generalized anxiety disorder (GAD) is a prevalent, chronic, debilitating mental illness associated with marked impairment in daily functioning.1 An ongoing evolution of the definition of GAD has resulted in a bifurcation of the historical anxiety neurosis designation.2 A diagnosis of GAD currently implies chronic, excessive worry lasting at least 6 months and 3 of the possible 6 somatic or psychological symptoms (restlessness, fatigue, muscle tension, irritability, difficulty concentrating, and sleep disturbance).3 GAD typically presents in an episodic pattern of moderate improvement or remission and relapse characterized by a chronic and complicated clinical course.
Chronic worry, a core component of GAD, is consistently found in 10% of the population, and this subset reports a level of anxiety and tension so significant that it markedly impairs daily function. Epidemiological studies, however, suggest a lifetime GAD prevalence of 4% to 7%, a 1-year prevalence of 3% to 5%, and a current prevalence of 1.5% to 3%.4 Discrepancies between the incidence of anxiety-related symptoms and potential subsequent underestimation of GAD prevalence may be attributed to DSM-IV diagnostic criterion of 6 months’ duration of worry.
It is the robust association of GAD with psychological and physical comorbidities that potentially contributes to the complexity of the illness as well as the limited treatment success.4,5 More than 90% of patients with GAD present with an additional psychiatric diagnosis. The ancillary condition is major depressive disorder (MDD) in 48% of patients.4,6
Three primary care studies found that pure GAD, defined as a current episode of GAD in the absence of any other mood, anxiety, or substance use disorder, was associated with meaningful levels of impairment in several life domains.7-10 Ormel and associates7 found that the mean numbers of disability days in the past month were much higher among primary care patients with pure GAD than among patients with none of the psychiatric disorders assessed in their survey. The 272 patients with pure GAD had more self-reported dysfunction in occupational role fulfillment and physical disability scores.
Traditionally, the goal of therapy has been to treat patients with GAD until a response is achieved. The response is either a clinically meaningful improvement in symptoms or a specific magnitude of change in a rating scale score from baseline. Given the extensive use of health care resources, the residual subsyndromal symptoms, and the substantial relapse rate of anxious patients, the goal of therapy has evolved to that of achieving remission.11
Remission is a dichotomous concept in that it is an absence or near absence of symptoms in addition to a return to premorbid functionality.11,12 Between 50% and 60% of patients respond clinically to therapy, but only one-third to one-half attain remission or realize full recovery during the acute phase of treatment.13 Some patients may achieve “durable remission” within the first 4 to 8 weeks of therapy, which may indicate an eventual sustained remission (lasting 4 to 9 months after acute treatment).12 Patients who achieve a sustained remission are less likely to experience relapse.14
Response to treatment and attainment of remission is comprehensively quantified both globally and specifically. The magnitude of treatment outcome is primarily measured by changes in the Hamilton Anxiety Rating Scale (HAM-A), the Clinical Global ImpressionImprovement (CGI-I) scale, and the total Sheehan Disability Scale (SDS). This multidimensional approach assesses disease-specific anxiety symptoms, quality of life, functioning, and nonspecific symptoms (avoidance).12 Response generally is defined as at least a 50% reduction in HAM-A score from baseline, and a “much improved” or “very much improved” rating on the CGI-I.11,12,15,16 Remission is defined as a HAM-A score of 7 or less, with global recovery achieved at a CGI-I score of 1 (“not ill at all” or “borderline mentally ill”), and functional recovery at an SDS score of 5 or less.14 For this designation of remission to be clinically meaningful, it must incorporate a time component. Remission is not static but rather should be sustainable over a considerable time—at least 8 consecutive weeks.17
The treatment of GAD involves a sequential process of first resolving the acute, symptomatic anxiety and then maintaining a longer-term constant suppression of chronic anxiety. Historically, benzodiazepines were the mainstay of GAD treatment, although the appropriateness of their use for long-term therapy is now under scrutiny.
Benzodiazepines indirectly affect the release and reuptake of monoamines via enhancement of the inhibitory effects of g-aminobutyric acid, thereby modulating fear, stress, and anxiety responses.18 Benzodiazepines are indicated for the short-term management of the acute phase of anxiety (2 to 4 weeks) as well as any subsequent exacerbations of anxiety during stable treatment. Their rapid onset and tolerability make them conducive to alleviating anxious symptoms when immediate anxiolytic effects are desired.19,20
A randomized, double-blind study compared response rates among patients treated with imipramine(Drug information on imipramine), trazodone, and diazepam(Drug information on diazepam). Patients in the diazepam arm had the most significant improvement in anxiety ratings within the first 2 weeks. Within this group, 66% of patients completing the study reported moderate to marked global improvement.21 Although more marked improvement was realized in the first 2 weeks of treatment with benzodiazepines, antidepressants consistently afforded the same efficacy as benzodiazepines or even surpassed them after 6 to 12 weeks of treatment, particularly in alleviating psychic symptoms.21,22
Aside from the obvious issue of potential dependence with prolonged use, benzodiazepines are not desirable as first-line therapy because of their potential for withdrawal syndromes and rebound effects on abrupt discontinuation.6,23,24 Yet, primary care providers have traditionally used benzodiazepines as first-line treatment of acute anxiety.20
The anxiolytic buspirone(Drug information on buspirone) has been used with moderate success but has not consistently demonstrated utility in any of the potentially comorbid conditions that can accompany GAD, with the exception of MDD.25,26 A retrospective analysis demonstrated significant improvement in HAM-A and global improvement scores relative to baseline, and another study reported buspirone’s failure to differ from placebo on numerous outcome measures.22,27,28 In addition, buspirone was shown to be superior to placebo in improving anxiety symptoms as well as coexisting depressive symptoms in patients with GAD. The significant anxiolytic effect resulted in more than a 50% response rate, based on reductions in the HAM-A score.29
Buspirone exerts its effect by reducing serotonin (5-HT) release as a partial agonist at 5-HT1A receptors in the hippocampus and as a full agonist at the presynaptic serotonergic auto-receptors.14,30 It has been shown to have comparable but slightly weaker efficacy than diazepam, clorazepate(Drug information on clorazepate), lorazepam(Drug information on lorazepam), and alprazolam(Drug information on alprazolam) and a slower onset of action.6 Its utility is mainly associated with its propensity to relieve the cognitive aspects, but it lacks long-term efficacy, particularly in managing the behavioral and somatic manifestations.14 In addition, patients who had been previously treated with benzodiazepines, especially recently, tend to have a muted response to buspirone (ie, a reduction in the anxiolytic effects).31
Tricyclic antidepressants (TCAs), such as imipramine, are typically more effective at attenuating the psychological symptoms of GAD as opposed to the somatic symptoms. Their inhibition of 5-HT and norepinephrine(Drug information on norepinephrine) reuptake produces anxiolytic and antidepressant effects. According to a study conducted by Rickels and colleagues,21 significant resolution of anxiety was achieved in patients who took imipramine between weeks 2 and 8 of therapy, and it afforded effects slightly superior to those of trazodone. Psychic symptoms of tension, apprehension, and worry were most effectively reduced in the imipramine arm: 73% of patients achieved moderate to marked improvement.21
The SSRIs are generally regarded as first-line medications, according to domestic and international practice guidelines.18,32 Paroxetine(Drug information on paroxetine), specifically, is FDA-approved for the long-term treatment of depression as well as for GAD at dosages of 20 to 50 mg daily. While the 2- to 4-week delay in onset of therapeutic effect may be discouraging, significant reductions in “anxious mood” have been documented as early as 1 week into treatment.
Remission rates in paroxetine responders at 32 weeks, admittedly a selected population of patients who persevere with treatment, are as high as 73%; relapse rates are only 11%. SSRIs have a sustained therapeutic effect and afford additional incremental improvement over a 24-week period.14,33 An 8-week, double-blind, placebo-controlled study examined paroxetine’s impact on HAM-A and SDS scores relative to baseline. The groups that received 20 mg and 40 mg of paroxetine demonstrated a statistically and clinically significant change in the HAM-A and psychic anxiety subscale relative to placebo.
In the intent-to-treat group, 62% in the 20-mg arm and 68% in the 40-mg arm met the criteria for response by week 8 (P < .001). Response rates were as high as 80% among patients who completed the study. Remission was achieved in 36% of the patients in the 20-mg group and 42% of the patients in the 40-mg group by week 8 (P = .004).22
An SSRI discontinuation syndrome, characterized by dizziness, insomnia, and flu-like symptoms, occurs in approximately 5% of patients on abrupt discontinuation or significant dose reduction.32 This typically manifests within 1 to 7 days of discontinuation in patients who have been taking an SSRI for at least 1 month.34 Of the SSRIs, paroxetine is most often implicated in withdrawal symptoms: about 35% to 50% of patients experience discontinuation symptoms on abrupt cessation.35 Reinstating the drug resolves symptoms of withdrawal relatively quickly.36 Tapering the SSRI dosage before discontinuation reduces the likelihood of this syndrome.
A promising alternative in first-line treatment in GAD therapy are the serotonin-norepinephrine reuptake inhibitors, which have been studied in both short- and long-term efficacy trials. Venlafaxine XR at a dosage of 75 to 225 mg daily consistently demonstrated superior efficacy versus placebo in improving anxiety symptoms by measure of a reduction in HAM-A total scores.37 The added benefit of venlafaxine’s efficacy in treating symptoms of anxiety in patients with comorbid anxiety and depression, in addition to pure GAD, has elevated its status in the treatment algorithm. Response rates approach 70%, and remission rates are as high as 43% short-term and as high as 61% long-term.14,38
The comorbidity of nonspecific somatic pain complaints is common in patients with GAD, which translates into a compounded negative impact on quality of life. A majority of patients (60%) with GAD and concomitant pain report that they experience a moderate to severe change in their somatic symptoms on days when they feel more anxious or depressed.39 Previous use of benzodiazepines was shown to reduce the probability of a response to venlafaxine in a study by Pollack and colleagues,40 although there was no substantial impact on attaining long-term remission.
Abrupt discontinuation of venlafaxine also precipitates a discontinuation syndrome with similar or greater frequency than does paroxetine.35 In addition, more diligent patient monitoring is required secondary to its propensity to precipitate hypertension.32
Duloxetine is indicated for the treatment of anxiety disorders, MDD, neuropathic pain, and fibromyalgia. Its dual impact on anxious symptoms and somatic pain resulted in 53% to 61% of treated patients who achieved a HAM-A score of 7 or less (symptomatic remission) and an about 47% who achieved an SDS score of 5 or less (functional remission).1,41 There is a positive correlation between improvement in pain scores and reduction in SDS scores: most patients who achieved remission also reported greater improvements in visual analog pain scales.39 Venlafaxine or an SSRI have been successfully used as initial monotherapy and long-term therapy; both have been shown to be equally effective.32
Patients with GAD are considerably more intolerant of normal uncertainty, which results in the formation of negative beliefs about uncertainty.42 Thus, these patients could benefit from psychosocial therapy. Numerous psychosocial treatment options are available as monotherapy or as adjunctive therapy in combination with a pharmacological agent. A psychosocial therapy that specifically addresses these cognitive aspects and trains patients to develop and apply coping skills that address psychological and somatic symptoms may be useful.43,44
Overcoming the barriers to remission
A multitude of factors are responsible for worsened outcomes and reduced probability of achieving remission in patients with GAD. Stressful life events, anxiety sensitivity, negative affect, gender, subsyndromal symptoms, and comorbidities all have a palpable impact on the course of illness and outcome. Frequently, patients elect to not complete long-term treatment and thus, life stressors may perpetuate subsyndromal symptoms. Although GAD is characterized by alternating periods of quiescence and exacerbation, the presence of comorbid depression, panic, or any Axis I or Axis II disorder, and a higher initial symptom rating, greatly lessens the possibility of remission.45-47 Pollack and colleagues40 found that restlessness predicted a worse treatment outcome, while sleep disturbance was typically associated with a more optimistic outcome.
Most patients who present with GAD have been ill for an average of 15 years before seeking help. As evidenced consistently by the literature, patients with GAD may decide to discontinue medication once they experience some improvement of symptoms.15 Unfortunately, once they respond positively to treatment, many patients will settle for that level of response instead of continuing therapy. This decision typically arises from fear of dependence on medication.15 Discontinuation of medication may briefly elicit a mild improvement, secondary to the psychological empowerment of self-management, but it will frequently lead to relapse.45 This drives the need for extensive patient education and clear, focused, patient-physician interactions.
Symptomatic remission traditionally precedes functional remission. Patient awareness of this fact should stem the inclination to discontinue therapy prematurely. Most of the first-line, long-term pharmacotherapies for GAD take 2 or more weeks to exert a full pharmacodynamic effect. The interval between the initial prescription of medication and a realization of effect may discourage adherence at an early stage. The likelihood of adherence can be increased by educating the patient about the expected onset of action and by prescribing a benzodiazepine at the start of long-term therapy.48
The majority of patients with GAD present to their primary care physician with a somatic complaint that is seemingly unrelated to GAD. This “masquerading” is another potential barrier to treatment.4 The inadvertent misdiagnosis of GAD or failure to identify a comorbid disorder results in poor treatment outcomes. Patients who are adherent and do not respond partially or fully to an appropriate medication may need to be reevaluated by a psychiatrist. Reevaluation may well lead to an alternative diagnosis and treatment regimen. Patients who present with predominantly depressive symptoms may be inaccurately labeled as depressed and treated accordingly. Treatment of depressive symptoms alone will not attenuate the somatic or functional aspects of GAD.49
Owing to the cyclical pattern of exacerbation and quiescence, many patients present for care during episodic exacerbations when symptoms are most debilitating. The risk is that the perceived acute anxiety will be treated as such, and the underlying, chronic anxiety will not be appropriately resolved.38 Inappropriate resolution of the chronic component of GAD will functionally impede remission and the prevention of relapse. Chronic pharmacotherapeutic treatment, as in MDD, is indicated for most patients who have GAD.
Whether early symptomatic improvement is a potential predictor of future response is currently being explored. A diminution in anxious symptoms within the first 2 weeks of drug therapy may predict remission. Pollack and colleagues11 found that significant improvement by week 2 of treatment translated into an increased likelihood of a clinical HAM-A response and remission of functional disability (SDS). Even moderate symptomatic improvement early on yielded functional remission by the end of week 2.
A constellation of factors influence the likelihood of attaining remission of GAD. The frequent presence of psychiatric or physical comorbidities complicates the clinical picture. Depression is the most prevalent of the psychiatric comorbidities and, as a result, incomplete treatment or misdiagnosis of GAD is often a root cause for treatment failure. Patient nonadherence, high initial symptom ratings, and interpatient variability in clinical presentation of GAD all contribute to the modest remission rates. Perhaps the most consequential factor in determining the propensity for success of GAD treatment is the use of an appropriate drug for an appropriate length of time. The duration of treatment is proportional to the magnitude of the outcome and the potential for realizing symptomatic and functional remission.
While not achievable in all patients, remission is the most appropriate therapeutic goal for GAD. Patients with personality problems and a multitude of comorbidities for whom the illness provides secondary gain may have difficulty in achieving remission. Although attaining remission is complicated by numerous treatment- and patient-related barriers, overcoming these challenges is feasible in the majority of patients. The diagnosis of GAD must be distinct from any other intervening psychiatric or somatic disorders. While the level of comorbidity is relatively high, the GAD diagnosis must be reliable and not confounded by other disorders. Treatment outcome goals must be clearly established in advance of therapy and should be based on the individual patient’s needs.
Psychotropic drug therapy for appropriate treatment duration is the foundation of successful therapy. A single drug is typically initially prescribed for patients who have GAD. Inadequate responses to monotherapy may warrant the addition of a second pharmacological agent or psychotherapy. Augmentation of drug therapy with benzodiazepines for 3 to 4 weeks and then gradually tapering the benzodiazepine may further reduce the reemergence of anxiety symptoms.6 Patients who demonstrate incomplete remission or lack of response need to be reevaluated in a timely manner to confirm the GAD diagnosis. In adherent patients for whom an appropriate duration of single drug therapy is unsuccessful, consider augmentation with a benzodiazepine or an anxiolytic with a different mechanism of action. The addition of a psychotherapeutic modality and/or a new pharmacological agent may generate additional benefit. Continuation of pharmacotherapy for 6 to 12 months beyond symptom resolution increases the likelihood of a sustained remission and decreases the likelihood of relapse.
Dr Mandos is assistant dean of pharmacy programs and associate professor of clinical pharmacy at the University of the Sciences in Philadelphia (USP) and clinical associate professor of psychiatry at the University of Pennsylvania School of Medicine. Dr Reinhold is assistant professor of clinical pharmacy at USP. Dr Rickels is Stuart and Emily Mudd Professor of Psychiatry at the University of Pennsylvania. The authors report no conflicts of interest concerning the subject matter of this article.
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