Ms. Schulz is psychiatry research project assistant, Dr. Gotto is director of consult/liaison services, and Dr. Rapaport is chairman in the Department of Psychiatry at Cedars-Sinai Medical Center in Los Angeles, CA. Dr. Rapaport is also vice chairman of the Department of Psychiatry and Behavioral Health at the David Geffen School of Medicine at the University of California—Los Angeles.

Disclosure: Ms. Schulz and Dr. Gotto report no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Rapaport is a consultant to Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, the National Institute of Mental Health (NIMH), the National Institute on Drug Abuse, Neurocrine Biosciences, Novartis, Pfizer, Roche, Sanofi-Synthelabo, Solvay, Sumitomo, and Wyeth; is on the speaker’s bureaus of Cyberonic, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Novartis, and Pfizer; has received grant support from Abbott, AstraZeneca, Corcept, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, the National Center for Complementary and Alternative Medicine, the NIMH, Novartis, Pfizer, Pharmacia Upjohn, Sanofi-Synthelabo, Solvay, the Stanley Foundation, UCB Pharma, and Wyeth; and owns stock in Forest.

Please direct all correspondence to: Julie Schulz, BA, Department of Psychiatry, Cedars-Sinai Medical Center, 8730 Alden Drive, Los Angeles, CA 90048. Tel: 323-449-1753; E-mail: runju32122@aol.com.


 

Abstract

Generalized anxiety disorder (GAD) is characterized by excessive anxiety and worry occurring over the course of ≥6 months. GAD has a 5.7% lifetime prevalence in the general adult population, and an 8% lifetime prevalance in the primary care setting. GAD is associated with twice the amount of primary care visits compared with patients without GAD, which leads to significant healthcare costs. This is largely because GAD commonly manifests with musculoskeletal, gastrointestinal, and cardiovascular physical symptoms. The course of GAD is chronic and disabling, with a low rate of spontaneous remission. Two thirds of patients with GAD have a secondary comorbid psychiatric diagnosis, with major depressive disorder being the most frequently occurring. Aggressive treatment is necessary to maximize resolution of symptoms. Fortunately, a variety of effective pharmacotherapies and psychotherapies exist for the acute treatment of GAD. Preliminary work suggests that these benefits are maintained with time and that continued pharmacotherapy may prevent the reoccurrence of GAD.  

 

Introduction

Anxiety disorders are the most common form of mental disorders in the United States.1 However, they are often missed because anxious patients typically approach primary care physicians (PCPs) with somatic complaints that obscure the underlying psychiatric diagnosis.2 Patients with generalized anxiety disorder (GAD) are more likely to complain of somatic symptoms than psychological symptoms. As a result, physicians often order costly diagnostic tests, unnecessary treatment trials, and referral for specialty evaluation.

GAD is characterized by excessive anxiety and worry occurring over the course of ≥6 months. Symptoms include restlessness, difficulty concentrating, irritability, muscle tension, sleep disturbance, and fatigue. Patients with GAD worry about physical illness, social and professional performance, interpersonal relations, personal safety, and the safety of people that are close to them. Somatic complaints of GAD patients typically fall into three categories: musculoskeletal, cardiovascular, or gastrointestinal.3 For example, a patient with GAD might complain of tachycardia, chest pain, diarrhea, and fatigue. The disorder is chronic, with periodic exacerbation, and causes significant distress and impairment.4 The spontaneous remission rate, or the rate at which patients recover from the disorder without treatment, is approximately 20% to 25%.5 This compares with a spontaneous remission rate of 32% for patients with major depressive disorder (MDD).6

Untreated GAD causes functional impairment similar to the disability seen in diabetes or congestive heart failure.7 In addition, people experiencing severe anxiety are at risk for suicidal ideation. According to the National Comorbidity Survey Replication (NCS-R), the adjusted odds ratio for lifetime suicidal ideation is .87 (.57-1.32, 95% CI), and the adjusted odds ratio for lifetime suicide attempts is 1.50 (.98-2.30, 95% CI).8 This article reviews the epidemiology, etiology, clinical presentation, diagnosis, clinical course, healthcare costs, and treatment of GAD, with an emphasis on its biological causes and treatment methods.

 

Epidemiology

The Epidemiological Catchment Area study reported that the lifetime prevalence of GAD (according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition [DSM-III]9) ranges from 4.1% to 6.6%.10 According to the NCS-R, which used DSM-IV11 criteria, GAD has a lifetime prevalence of 5.7% in the US adult population.2  While the age of onset of GAD peaks during the second and third decades,12 first onset of the disorder can occur at any age. Ten percent of GAD patients experience onset of the disorder at <13 years of age, and 10% experience onset of GAD at >51 years of age.12 The 12-month prevalence rates of GAD range from 0.5% to 1.5%.13,14 Women are at twice the risk of developing GAD as men.2

Recognition and treatment of GAD are especially important in the primary care setting since GAD is common and is associated with significant use of medical resources. In one study performed in a primary care setting, GAD was diagnosed in 8.0% of patients.15 In a second study performed in a primary care setting, 3.7% of adult patients met criteria for current GAD and 6.6% presented with subthreshold anxiety symptoms.16 In a third study, 5.3% of the patients seen in primary care met criteria for current GAD.17 Thus, the point prevalence rate for GAD is 3.7% to 8.0% for patients screened in primary care settings.

 

Comorbidity

Only one third of people with a current diagnosis of GAD have no other comorbid psychiatric diagnosis.2,18 In fact, Noyes19 suggests that the rates of comorbid psychiatric disorders might be greatest for patients with GAD. MDD (11% to 47%) is the most common comorbid disorder.19 The National Comorbidity Survey data suggest that preexisting anxiety disorder is a risk factor for depression, and anxiety precedes the onset of depression by about 10 years.2 Social anxiety disorder (17% to 59%), specific phobia (15% to 56%), and panic disorder (11% to 27%) are the most prevalent secondary anxiety disorders diagnosed in patients with GAD.20-25  

Personality disorders are thought to coexist in approximately 60% of patients with GAD.26,27 The most common personality disorders diagnosed in patients with GAD are obsessive-compulsive personality disorder (33.5%), paranoid personality disorder (30.5%), and avoidant personality disorder (21.9%).27

The presence of psychiatric comorbidity increases the severity of GAD and complicates the treatment course for these patients.28 However, the presence of psychiatric comorbidity also increases the likelihood that patients will seek psychiatric care.29

 

Evolution of the Generalized Anxiety Disorder Diagnosis

The DSM-IV definition of GAD has evolved over the last 125 years. Prior to the DSM-III, the concept of anxiety was amorphous, lumping Freud’s “neurosis” together with phobias and panic attacks.30 The DSM-III-defined generalized anxiety as “uncontrollable anxiety of worry that is not due to a particular life problem,” has a duration of 1 month, cannot be diagnosed in the presence of another mental disorder, and requires the presence of autonomic symptoms. Changes in the DSM-III-R31 definition of GAD required lengthening the duration of symptoms (1 month was changed to 6 months), the presence of six physical symptoms, and the caveat that the anxiety could not be due to another anxiety disorder. In the DSM-III-R, GAD can be diagnosed in the presence of another mental disorder. The DSM-IV criteria require that only three of six physical symptoms be present, and these symptoms must be equally psychologic and somatic (Table 1).

 

Clinical Presentation

Core features of GAD include excessive anxiety or worry occurring more days than not, over a period of 6 months. These worries may be associated with several events or activities, including job responsibilities, finances, health of friends and family members, safety of children, household chores, car repairs, or tardiness. Patients experience impairment in social, occupational, or other important areas of functioning related to the worries. Individuals with GAD find it difficult to control such worry. The frequency, intensity, and duration of anxiety are out of proportion to the likelihood or impact of a feared event.

A list of common somatic symptoms associated with GAD is presented in Table 2. Patients with anxiety often seek initial treatment from their PCP. However, GAD is frequently not recognized in the primary care setting. In a recent study, PCPs recognized and diagnosed pure GAD in only 34% of patients with the disorder.32

Individual and cultural characteristics may influence the presentation of GAD. Some patients complain primarily of cognitive symptoms such as confusion, perceptual distortion, difficulty concentrating, and indecisiveness. Other patients may express anxiety predominantly through somatic symptoms. While it is accepted that the initial clinical presentation of anxious symptoms may range from cognitive to somatic complaints, the full effect of cultural and personality factors on both the presentation and treatment course of anxiety are not well understood. A review of the subject of cultural effect on anxiety disorders showed that in general, opinions on this topic are mixed.12,33 Cultural attitudes toward mental health, language nuances, and socioeconomic factors all have the potential of affecting a person’s experience of anxiety. This experience may affect the way in which a particular patient presents his or her ailments to the physician. There is a paucity of research on the cultural differences in the presentation of GAD, and this topic merits further study.

Although it is sometimes challenging to differentiate normal concern from pathological anxiety, a key finding about anxiety disorders is that the intensity and distress associated with the worry  far exceed any stimulus. A person with GAD is a “worry wart” with widespread, intense, and persistent anxiety that occurs without an identifiable trigger. Individuals with GAD palpably feel their anxiety, are disabled by it, and have diminished quality of life.

 

Clinical Course

While the median age of onset of GAD is 31 years, 10% of GAD patients first experience the disorder at <13 years of age, and 10% experience it after 58 years of age.12 Early-onset patients are more likely to develop GAD without precipitating events, and are more likely to have been exposed to domestic disturbances in childhood. These patients report heightened anxiety during childhood, childhood fears and obsessional traits, sensitivity to interpersonal relationships, and social inhibition and maladjustment.33 In contrast, late-onset GAD is associated with a precipitating adverse life experience.33 The development of a full-blown anxiety disorder often occurs when an already anxious person is subjected to great life stress, such as losing a job or taking on a second mortgage.

The severity of symptoms of GAD and impairment may fluctuate considerably over an individual’s lifetime. The symptoms are often more severe when exogenous stressors are present. In women, symptoms may be exacerbated premenstrually. It is clear that for the majority of patients, extended periods of remission are unlikely without vigorous treatment.

GAD has a chronic course. Treatment should be continued on a long-term basis in order to maximize resolution of symptoms, remediate functional disability, and increase the intervals between episodes of illness.34 The longer term spontaneous remission rate is low for GAD, with a .38 probability of remission at 5 years.35 The 12-year follow-up results from the Nottingham Study found that 59% of the patients originally diagnosed with GAD (using DSM-III criteria) were symptomatic at follow-up.36 Of the patients originally diagnosed with GAD, the most common diagnoses after 12 years were dysthymic disorder (18%) and major depressive episode (10%). Only 3% had a diagnosis of GAD. Thus, people with GAD are at significant risk for developing depressive disorders.  The Harvard-Brown Anxiety Research Program found that 60% of subjects identified with an index episode of GAD had active GAD at 2-year follow-up. At 5-year follow-up, 66% of index cohort was classified as having either GAD or GAD in partial remission.37

 

Disability and Healthcare Utilization

Patients with GAD have twice the rate of primary care visits compared to primary care patients without GAD.32 Patients with comorbid GAD and other Axis I disorders have greater rates of hospitalization, greater utilization of diagnostic and laboratory tests, higher pharmacy costs, and more absenteeism from work than patients with GAD without any psychiatric comorbidity.38 In fact, comorbid GAD is commonly associated with a number of physical disorders, such as irritable bowel syndrome. The prevalence of comorbid GAD ranges from 13% to 25% in patients with irritable bowel syndrome.39,40

Biological Etiology

Relatively few studies have addressed the biological aspects of GAD. The development of a sound biological basis for GAD, distinct from other anxiety or mood disorders, has been complicated by three major factors. First, while there are animal models available for stress and anxiety, there is no true animal model specific for GAD. Second, the pharmacologic probes available for investigating the neurobiology of GAD are relatively insensitive to their targets. Finally, the lack of a consistent definition for GAD makes it difficult to compile studies using the same criteria. Many studies investigating the biology of GAD use DSM-III or DSM-III-R criteria for diagnosis.

A significant portion of the biological research investigating GAD is based on the success of pharmacologic treatments. Since these interventions tend to be effective across most of the anxiety disorders, it is challenging to identify neurotransmitter abnormalities that may be specific to GAD. In fact, many clinical studies now address behavioral or symptomatic phenomena that cut across several diagnoses, rather than focusing on a single disorder.

 

Molecular Biology

It is generally accepted that dynamic interactions among several different neurotransmitter systems are likely to underlie different anxiety states. Evidence from animal and human studies suggests that alteration of function of the γ-aminobutyric acid (GABA) neuronal system plays a significant role in the pathophysiology of GAD. Benzodiazepine receptors (BDZ-Rs) and GABAA receptors are part of the same macromolecular complex. Animal studies suggest that GABAA receptor dysfunction plays a role in the development of GAD.41 In addition, clinical studies have shown that benzodiazepines are effective in treating patients with GAD.42 Patients with GAD have been shown to have low levels of peripheral benzodiazepine receptors (pBR) and low levels of pBR messenger ribonucleic acid in lymphocytes.43 These levels increased to normal after 2 months of treatment with a diazepam-related compound, and remained normal up to 1 month after discontinuing treatment. In this study, the level of pBR was also correlated with the amount of clinical improvement. These results suggest that the lower expression of pBR is a state-related biological abnormality in patients with GAD that can be remediated with appropriate treatment. However, the mechanism by which the levels of pBRs are normalized is still unknown and one must always be careful when extrapolating from studies of the pBRs to the function of the central BDZ-Rs.

Medications that affect serotonin and norepinephrine, neurotransmitters  thought to be central to the pathophysiology of GAD, prove efficacious. However, research investigating these neurotransmitters is inconsistent. One study found elevated plasma levels of norepinephrine and decreased α2-adrenergic function in GAD patients.44 The authors of that study concluded from these findings that norepinephrine activity is elevated in GAD, causing receptor downregulation. Other studies were unable to replicate these findings.45,46 The one investigation exploring the metabolic pathways of catecholamines failed to find a difference between GAD subjects and normal controls,47 and studies have failed to consistently demonstrate that plasma catecholamine levels of GAD subjects are higher than normal comparison subjects.45,46 Furthermore, research investigating catecholamine receptors in GAD patients are mixed and inconclusive.48-50 In summary, there is little evidence suggesting abnormalities in the catecholamine system for patients with GAD.

Studies investigating the role of serotonin in GAD are also inconclusive. Both overactivity or underactivity of the serotonergic system has been hypothesized to be involved in the pathogenesis of GAD.51,52 Some of the strongest biological evidence linking the serotonin system and GAD have been studies with the serotonin receptor agonists buspirone, ipsapirone, and gepirone. These agents decrease the firing rate of serotonergic neurons and exert anxiolytic effects in patients with GAD.53

The hypothalamic-pituitary-adrenal  axis has been implicated in other anxiety disorders and may play a role in GAD. Cortisol, the primary hormone implicated in stress, has been shown to be elevated in GAD patients.54 In normal subjects, exogenous cortisol induces an increase in the serotonin transporter gene transcription.55 However, the incubation of peripheral lymphocytes from GAD patients with cortisol failed to increase serotonin transporter gene product.55 Corticotropin-releasing factor (CRH) is associated with heightened states of anxiety in animal models. However, there is no conclusive association between CRH dysfunction and GAD.56-58

 

Genetics

Genetic studies suggest a moderate degree of heritability for GAD. The prevalence rate for GAD is 20%59 to 22%60 for individuals who have a first-degree relative with GAD, as compared to a 4% prevalence rate in the control sample.59 Twin studies demonstrate that 21% of monozygotic twins are concordant for GAD, versus 13% of dizygotic twins.61 Candidate genes for further study include those influencing norepinephrine and serotonin neurotransmission as well as GABA and CRH. Of particular interest is the serotonin transporter gene located on chromosome 17q. One study reported that polymorphism in the second intron of this gene occurs at significantly higher rates in individuals with GAD.62

 

Treatment Options in Generalized Anxiety Disorder

There are evidence-based pharmacologic and psychologic treatment options for GAD (Table 3). Ideally, the physician and patient should work together to define the problem and the treatment plan. It helps to get the patient’s dedication to the treatment plan, and for the patient to understand that improvement may take months or even years. The patient should be aware that the course of GAD waxes and wanes, and that complete remission is unlikely. Treatment should be individualized for each patient, with the patient’s symptom profile and ability to tolerate side effects as the primary considerations. Other treatment factors may include history of previous treatment and response, presence of comorbid depression or other anxiety disorders, presence of Axis II disorder, presence of comorbid medical condition, and history of substance abuse. There are no clear evidence-based guidelines for determining the length of time a patient should receive a particular treatment. A review of eight long-term GAD treatment studies was inconclusive, and no drug was identified as a reference for long-term treatment.63 It is generally recommended that treatment continue for 1 year after the patient responds to it before considering cessation.64

 

Pharmacologic Therapies

Benzodiazepines

Benzodiazepines are a well-studied class of medications with proven efficacy in the treatment of GAD.65 Approximately 75% of patients have either a marked (35%) or moderate (40%) response to treatment.66 Anxious symptoms respond to benzodiazepines rapidly, with the most dramatic improvement occurring in hypervigilance and somatic symptoms, such as muscle tension, restlessness, and insomnia. Psychological symptoms, such as worrying and fretting, are not as responsive to benzodiazepine medication, and may require additional treatment with cognitive-behavioral therapy (CBT) or another specific modality.

Mechanism of Action

Benzodiazepines exert their effect at BDZ-Rs, which are located throughout the brain in the cerebellum, limbic system, and cerebral cortex. The BDZ-R is structurally linked with the GABA receptor. When GABA is present at the GABA receptor, chloride ions pass through a channel into the neuron, which hyperpolarizes the cell membrane. This results in decreased firing, which “quiets” the cell. A benzodiazepine, when present at the BDZ-R, potentates the GABA-induced opening of the chloride channels. GABA must be present at the GABA receptor in order for benzodiazepines to work. This explains why an overdose on a benzodiazepine alone is usually not fatal; the body has a finite supply of GABA. However, if a benzodiazepine overdose is combined with a substance that opens chloride channels without needing to bind to a receptor (such as alcohol or phenobarbital), then a benzodiazepine overdose can result in central nervous system depression and death.

The main differences between benzodiazepines are their half-life and potency. Half-life is important when considering dosing; a medication with a short half-life, such as alprazolam, may require multiple daily dosing, whereas clonazepam, with a half-life of 34 hours, may be given QD or BID. Benzodiazepines with shorter half-lives are more likely to be associated with “clock watching.” This occurs when an anxious patient notices the anxiolytic effect of medication is wearing off, and watches the clock, counting the minutes until the next dose. Shorter-acting benzodiazepines are also associated with interdose rebound anxiety, greater potential for abuse, and greater risk of withdrawal syndromes.    

Absorption and the onset of action are most rapid for diazepam, lorazepam, alprazolam, triazolam, and estazolam.  The rapid-onset medications are useful in patients who use benzodiazepines on an as-needed basis for a burst of anxiety or for falling asleep.

The 2-keto benzodiazepines (Table 4) have half lives of 30–120 hours. This occurs because they are all metabolized to desmethyldiazepam, which is pharmacologically active and takes a long time to break down to oxazepam and then to a form that can undergo glucuronidation.67

The half-lives of the 3-hydroxy benzodiazepines are much shorter, at 10–30 hours. This is because they are directly metabolized by glucuronidation and have no active metabolites.  Alprazolam and triazolam are triazolobenzodiazepines that are hydroxylated prior to undergoing glucuronidation.  

Benzodiazepines are generally well tolerated. Side effects such as somnolence, fatigue, reduced concentration, and slowed psychomotor function may occur early in treatment, and can be handled either by dose reduction or changing the time the medication is taken. Patients usually develop tolerance to the sedating side effect of benzodiazepines after 7–10 days of treatment. Although patients become tolerant to the side effects of benzodiazepines, they do not develop tolerance to the anxiolytic effect of the medication.68 It is unclear how long therapy with a benzodiazepine should continue. Recent recommendations suggest a treatment trial of 6 weeks using the lowest possible effective dose, and then making an attempt to taper the medication dose. The reason for the 6-week time frame is that approximately 50% of patients do not relapse after 6 weeks of treatment with benzodiazepines.69 Given this, the clinician should instigate an initial taper after 6 weeks to see if the patient is one of the 50% of patients who tolerate early benzodiazepine discontinuation. If the patient does not tolerate the taper and experiences a relapse, then treatment resumes for a longer period of time. A second attempt at benzodiazepine discontinuation with a slower taper may be tried. If the patient still experiences relapse, that patient may require longer-term therapy, or the addition of antidepressant medication or CBT.

Even though the majority of patients do not escalate their dose or abuse their medication,70 the long-term use of benzodiazepines for anxiety remains controversial. There are several reasons for this. Physicians are concerned about the long-term side effects and the abuse potential of benzodiazepines. In reality, patients with anxiety typically are wary of becoming dependent on medication. The tolerance that occurs with chronic benzodiazepine use may be confused with the idea of drug dependence, and this may be unsettling for GAD patients. If a patient treated with twice daily alprazolam is admitted to the hospital for a medical illness, this patient is at great risk for rebound anxiety and even benzodiazepine withdrawal unless the admitting physician is aware of the patient’s anxiety disorder and specific treatment. Even then, a well-intentioned physician might schedule the alprazolam as needed when the patient has been using it regularly, thus setting the anxious patient up for potential demise. The withdrawal that occurs with the shorter-acting benzodiazepines can occur remarkably fast, as the patient’s mental state may move from anxious to agitated to psychotic to delirious within 48–72 hours of the last missed dose.

The benzodiazepines that undergo rapid metabolism and have no active metabolites (lorazepam, oxazepam) are safer choices when using benzodiazepines in the elderly or in patients with liver or respiratory disease. The elderly are at risk for confusion, falls, and becoming paradoxically agitated when exposed to benzodiazepines, so these medications should be used judiciously in these patients. Benzodiazepines should be used with caution in any medically ill patient, though they are quite useful in treating anxiety associated with procedures or anxiety due to certain medications.  

 

Antidepressants

Tricyclic Antidepressants and Monoamine Oxidase Inihibitors

Over 2 decades of data demonstrate that antidepressants are effective in the treatment of GAD. Since anxiety and depression commonly coexist, this makes antidepressant pharmacology an efficient option for treating both problems. Most of the studies using tricyclic antidepressants (TCAs) in anxiety are older, and the criteria used for GAD are less strict than in the more recent DSM-IV-based studies, so it is possible that patients included in the earlier studies may have had disorders other than GAD. In any case, the TCAs are at least as effective as benzodiazepines in the short-term management of anxiety,71 and are more effective in reducing the psychic symptoms of anxiety.72

TCAs work by inhibiting the reuptake of norepinephrine (NE) and serotonin (5-HT), thereby increasing the available amount of both neurotransmitters in the synaptic cleft. The TCAs differ in their abilities to inhibit NE and 5-HT.  For example, clomipramine is considered to be a “serotonergic” tricyclic. The tricyclics, like the selective serotonin reuptake inhibitors (SSRIs), are useful in treating the patient with mixed anxiety and mood disorder, where anxiety and mood pathology coexist.

The clinical utility of the TCAs is limited by their side-effect and safety profile. The typical TCA side effects, which include dry mouth, constipation, blurred vision, passing out, or gaining weight, may be more than anxious patients want to tolerate. This class of agents has anticholinergic, antiadrenergic, and antihistaminic side effects.  The monoamine oxidase inhibitors (MAOIs), are used in the treatment of atypical depression, panic disorder, and as an alternative therapy in treatment-resistant depression. MAOIs are known to reduce anxiety when used in the treatment of depression. They work by irreversibly inhibiting monoamine oxidase, the enzyme that breaks down NE, dopamine, and 5-HT. MAOIs are infrequently prescribed. In a 1999 survey of prescribing practices, Balon and colleagues73 found that although 92% of respondents believed MAOIs are useful for atypical depression, only 2% said they would use them as a first-line treatment. MAOIs have fallen out of favor due to side effects and dietary restrictions. Moclobemide, a reversible MAOI, is an effective treatment for depression and does not carry the risk for tyramine reaction. However, it is not available in the US.

 

Selective Serotonin Reuptake Inhibitors

There is great deal of placebo-controlled evidence supporting the efficacy of SSRIs as a treatment for GAD. Clomipramine was the first TCA “serotonergic” agent studied for the treatment of GAD; the study was an 8-week open trial where 10 subjects were treated with doses ranging from 50–250 mg/day.74 Five subjects dropped out because of the clomipramine side effects. The remaining five subjects had a good response to the medication.  

The first controlled study of an SSRI compared the outcomes of 81 patients with DSM-IV-based GAD treated with paroxetine 20 mg/day, imipramine 75 mg/day, or 2-chlordesmethyldiazepam 4.2 mg/day.75 Two thirds of patients in all three treatment groups improved moderately or markedly (imipramine, 67%; paroxetine, 68%; 2-chlordesmethyldiazepam, 60%). In a multi-center, double-blind, placebo-controlled trial, 566 patients with DSM-IV-diagnosed GAD were treated with paroxetine 20 mg/day, paroxetine 40/day, or placebo. Paroxetine 40 mg alleviated symptoms better than paroxetine 20 mg, and both were superior to placebo.76 In another placebo-controlled study of 324 outpatients with DSM-IV-diagnosed GAD, a flexible dose of paroxetine (20–50 mg/day) was compared to placebo. The patients treated with paroxetine experienced improvement of core symptoms of GAD as early as 4 weeks, and a reduction in disability compared to patients treated with placebo.77

One double-blind, placebo-controlled study of citalopram 20–30 mg/day in 34 older (≥60 years of age) outpatients with mostly DSM-IV-diagnosed GAD found that 65% of patients responded by 8 weeks of treatment with citalopram versus 24% of patients treated with placebo. The most common side effect experienced by the treatment group was sedation.78 A study of escitalopram, the s-enantiomer of citalopram, compared 8 weeks of treatment with escitalopram 10–20 mg/day to placebo in 315 patients with GAD. Sixty-eight percent of escitalopram-treated subjects responded, compared to 41% of patients treated with placebo.79 There was one double-blind, prospective trial comparing 8 weeks of paroxetine to sertraline in the treatment of 55 patients with GAD.80 This comparison found that both SSRIs equally reduced Hamilton Rating Scale for Anxiety (HAM-A) scores (paroxetine 57%±28%, and sertraline 56%±28%) and were similarly well-tolerated.

 

Mechanism of Action   

SSRIs work by inhibiting the reuptake of serotonin so that more serotonin is available in the synaptic cleft. It is unclear exactly how this increase affects changes in anxiety and mood. The SSRI antidepressants are better tolerated than the TCAs, and are safer in overdose situations. Anorgasmia is a significant side effect of SSRI therapy, and occurs in both genders. There are several possibilities for dealing with this problem. Dose reduction may help in some cases. Adding a small dose of trazodone, bupropion, or buspirone may be helpful in others. Some patients respond to sildenafil therapy, as needed. If none of these interventions work, the patient and physician should weigh the benefit of treating the anxiety with the current SSRI versus adequate sexual functioning. Sometimes switching to a different SSRI medication may improve symptoms. CBT is an option for patients who decide to taper off SSRI medication.  

Other side effects of SSRI therapy include initiation activation, restlessness, nausea, and diarrhea. Starting patients on a very low dose of SSRI and increasing the dose slowly averts initiation activation. Alternatively, starting a benzodiazepine simultaneously with the SSRI may also prevent initiation anxiety. The benzodiazepine can be tapered and discontinued once the SSRI dose is within a therapeutic range.

 

Serotonergic Noradrenergic Reuptake Inhibitors

Venlafaxine, a serotonergic noradrenergic reuptake inhibitor, is the best studied antidepressant medication used in the treatment of GAD. In a series of placebo-controlled, randomized, short-term treatment trials comparing venlafaxine extended release (XR) to placebo, venlafaxine was consistently superior to placebo in improving both somatic and psychic symptoms of anxiety. In one study that compared venlafaxine XR 75 mg and 150 mg, buspirone 30 mg, and placebo, both venlafaxine doses improved anxious mood and tension indices by week 8, and both venlafaxine doses were better than placebo and more effective than buspirone after week 1.81 Another 8-week, randomized, placebo-controlled study evaluated fixed doses of 75 mg, 150 mg, or 225 mg venlafaxine XR against placebo and found that venlafaxine was consistently superior to placebo on all of the primary outcome measures. The most robust improvements were seen with the higher doses.82 An 8-week, double-blind, placebo-controlled study of Greek outpatients with GAD compared flexible dosing of venlafaxine XR (75–150 mg) with placebo, and found that the 62.5% of venlafaxine-treated patients achieved remission versus 9.1% in the placebo group. Remission was defined as a HAM-A score ≤7.83

The long-term studies of venlafaxine validate the clinical lore that the improvements gained in the acute treatment phase can be maintained and even enhanced over a longer period of time. The first long-term study evaluated flexible dosing of venlafaxine XR over 6 months. In this study, 251 patients were assigned to receive either venlafaxine XR at doses between 75 mg/day and 225 mg/day to control symptoms, or placebo. Venlafaxine XR was superior to placebo with a response rate of 69% from week 6 through week 28, versus placebo response rates of 42% to 46%.84 Another 6-month, fixed-dose trial comparing venlafaxine XR 37.5 mg/day, 75 mg/day, or 150 mg/day with placebo found that in the short term (8 weeks), both the 75-mg and 150-mg dose groups showed significant differences from placebo on all of the primary outcome measures. The outcome measures included the HAM-A total score, the HAM-A psychic anxiety factor, the Hospital Anxiety and Depression (HAD) anxiety subscale and the Clinical Global Impressions (CGI) Improvement rating. At 8 weeks, the 37.5-mg dose was only significantly better than placebo on the HAD anxiety subscale.  After 24 weeks of treatment, the greater efficacy for the higher venlafaxine doses was preserved over both placebo and the 37.5-mg dose. The higher doses also demonstrated improved social functioning by the Social Adjustment Rating Scale compared to placebo.85

Like the TCAs, venlafaxine works by inhibiting the reuptake of serotonin and norepinephrine. It lacks the anticholinergic, antiadrenergic, and antihistaminic effects of the TCAs, and is consequently better tolerated. Somnolence, nausea, and dry mouth are the side effects most commonly reported. Anorgasmia may also occur as a side effect of venlafaxine treatment. Venlafaxine needs to be tapered when discontinued.     

 

Other Antidepressants

Trazodone

Little evidence supports the role of trazodone for the treatment of GAD. One 8-week, randomized, placebo-controlled trial comparing imipramine, trazodone, and diazepam in 230 patients with a DSM-III diagnosis of GAD, found trazodone to be more effective than placebo. In this study, diazepam was initially the most effective, especially against somatic symptoms, but by the end of the 8 weeks a moderate-to-marked improvement was reported by 73% of imipramine-treated patients, 69% of trazodone-treated patients, 66% of diazepam-treated patients, and 47% of the placebo group. Both the imipramine and trazodone groups had a better response on measures of tension, apprehension, and worry.71 Trazodone’s mechanism of action is not well understood; it is believed to work by inhibiting the reuptake of serotonin, and by acting as an antagonist at the serotonin receptor 5-HT2A/1C.  

 Nefazodone is an antidepressant with activity similar to both SSRIs and trazodone. There is evidence to suggest that nefazodone is a reasonable treatment option for GAD. One open trial of 21 patients with DSM-IV-based GAD were treated with nefazodone for 8 weeks. Of the 15 patients who completed the trial, 80% were rated as both very much or much improved, 7% as minimally improved, and 13% as unchanged.86 Unfortunately, nefazodone is associated with an elevation in liver enzymes that has led to a black box warning. This has diminished its use. 

Mirtazapine, a noradrenergic and specific serotonergic antidepressant, has a dual mechanism of action. It binds to and inhibits the α2 autoreceptor and the α2 heteroreceptor, which prevents negative feedback of synaptic noradrenaline on 5-HT and noradrenaline receptors. This results in enhanced serotonergic and noradrenergic activity. Mirtazapine also blocks 5-HT2 and 5-HT3 receptors on the postsynaptic membrane, which results in enhanced 5-HT neurotransmission. There was one 8-week, open-label trial of mirtazapine in patients with comorbid MDD and GAD. In this study, 10 patients were initially treated with mirtazapine 15 mg, which was titrated up to a maximum of 45 mg/day. Significant improvement in HAM-A and Hamilton Rating Scale for Depression scores occurred after the first week of treatment and persisted throughout the rest of the study.87

 

Buspirone

The clinical evidence for buspirone in the treatment of GAD is fairly extensive. There are 15 double-blind, placebo-controlled trials of buspirone, most of which compare it to a benzodiazepine, placebo, or both. Buspirone was more effective than placebo in 10 of these studies, but was never more effective than benzodiazepines.30 One study reanalyzed previous study data of 735 patients with DSM-III GAD treated with either placebo, buspirone, or a benzodiazepine to determine whether or not prior treatment with benzodiazepines might predict a poorer response with buspirone.  The results showed that patients with recent benzodiazepine treatment report much less improvement with buspirone than patients who are benzodiazepine-naïve, or patients who have a remote history of benzodiazepine treatment.88

Buspirone acts by modulating the serotonergic system. It has activity as a full agonist at the presynaptic 5-HT1A, where it inhibits serotonin synthesis and firing of the raphe nucleus. It acts as a partial agonist at the postsynaptic 5-HT1A, which results in increased receptor activity.89 Buspirone provides a nonbenzodiazepine option for the treatment of GAD, and may be useful in the benzodiazepine-naïve patient. Unfortunately, the population most likely to be prescribed buspirone, patients with comorbid alcohol, personality, or substance abuse disorders, are the least likely to feel its antianxiety effects. Buspirone has a slow onset of action, and may take several weeks to demonstrate a significant clinical effect. It may be difficult for an anxious patient to wait for the anxiolytic effect. Additionally, buspirone does not improve insomnia, which is a common complaint in GAD.  

 

Other Medications

A few French studies demonstrate some efficacy for hydroxyzine in the treatment of GAD. Hydroxyzine works by competetively blocking the effects of histamine at H1 receptor sites. One 4-week, double-blind, placebo-controlled study compared hydroxyzine 50 mg/day to placebo in 133 patients with DSM-III GAD. The hydroxyzine group had significantly more improvement on measures of anxiety. However, 52% of the treatment group complained of sleepiness, weight gain, dry mouth, and loss of concentration, all common antihistamine-related side effects.90 A longer, 3-month, double-blind, placebo-controlled, randomized trial comparing hydroxyzine 50 mg/day, bromazepam 6 mg/day, and placebo found that hydroxyzine was as effective as bromazepam and more effective than placebo in reducing CGI severity scale scores and HAD scores.91 Finally, a European multicenter, double-blind comparison of hydroxyzine 50 mg, buspirone 20 mg, and placebo found that only hydroxyzine was significantly better than placebo on the HAM-A, which was the primary outcome measure. Both hydroxyzine and buspirone were more effective than placebo on CGI and HAD ratings. However, this study is confounded by the idiosyncratic dosing of buspirone.92

Kava kava, a compound from a plant that grows in the Pacific Islands region, is reported to have analgesic and anxiolytic properties. It is also reported to inhibit monoamine oxidase B.93 However, the evidence supporting its use in the treatment of GAD is scant. An 8-week, randomized, double-blind, German trial treated 129 GAD patients with either 400 mg Kava LI 150, buspirone 10 mg, or opipramol 100 mg. There were no significant differences between any of the outcome measures in 127 of the treated patients. Seventy-five percent of patients were classified as responders and 60% achieved remission.94 Another study that compared kava kava against placebo in 37 patients with DSM-IV GAD found that improvements occurred in both treatments, and kava did not differ significantly from placebo.95 Studies of kava kava have been discontinued because of concerns about hepatoxicity.

 

Psychotherapies

CBT has been demonstrated to be an effective treatment for GAD. A study comparing nondirective therapy, CBT, and applied relaxation in outpatients with GAD found that both applied relaxation and CBT were superior to nondirective therapy by the end of the study. Longer-term follow-up of the subjects determined that the nondirective therapy group had lost its treatment gains, but both CBT and applied relaxation maintained their treatment gains, with the greatest gains maintained by the CBT group.96 Another study comparing CBT, behavior therapy, and a wait-list control group found that CBT was consistently more effective than behavior therapy on measures of cognition, mood, and anxiety.97

Although psychodynamic psychotherapy was employed for years in the psychotherapeutic treatment of anxiety, there is no evidence to support its efficacy in the treatment of GAD.

 

Conclusion

GAD is a common disorder and is highly comorbid with other psychiatric syndromes. GAD alone and GAD comorbid with other psychiatric syndromes is remarkably disabling and significantly impedes on the quality of life of individuals and their loved ones. At this time, little is understood about the biology of GAD, but it is hoped that advances in neurobiology and genomics will enhance our knowledge about the pathogenesis of this syndrome. Patients with GAD commonly approach PCPs with somatic concerns such as headaches, backaches, and muscle spasms. Fortunately, there are safe and effective pharmacotherapies and psychotherapies for GAD. However, the longer-term prognosis for GAD is still troubling. This emphasizes the need for more longitudinal treatment research as well as exploration of alternative modalities of therapy.  PP

 

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