An overview of generalized anxiety disorder: disease state—appropriate therapy

CLINICAL THERAPEUTICWVOL.

22, SUPPL. A, 2000

An Overview of Generalized Anxiety Disorder: Disease State-Appropriate Therapy R. Bruce Lydiurd, PhD, MD Institute of Psychiatry, Medical University of South Carolina, Charleston, South Carolina

ABSTRACT

Objective: This article reviews the prevalence, diagnosis, and treatment of generalized anxiety disorder (GAD). Background: Patients with GAD often present to primary care physicians; frequently the disorder manifests with somatic symptoms that have no identifiable physiologic foundation. Accurate diagnosis and treatment often prove elusive, and health care resources are inappropriately consumed in the management of a wide array of complaints, including headache, noncardiac angina, fatigue, insomnia, or abdominal discomfort. Early diagnosis and intervention are critical; GAD is frequently associated with other anxiety and mood disorders, major depressive disorder among them. The differential diagnosis of GAD is complex, including medication side effects and substance-related dependence or withdrawal phenomena, as well as endocrine, neurologic, cardiorespiratory, and autoimmune disorders. Conclusions: GAD is differentiated from adjustment disorder with anxiety because only GAD can manifest without identifiable emotional stressors; it is differentiated from panic disorder largely on the basis of the chronicity of GAD and the episodic, abrupt nature of panic attacks, with the involvement of at least 4 autonomic, cardiopulmonary, neurologic, or other symptoms. In addition to psychotherapy, education, lifestyle modifications, and social support, several pharmacologic agents may be appropriate therapy for GAD. Given the chronic, nonremitting, relapsing character of GAD, use of benzodiazepines, which confer short-term relief, is usually ill-advised in long-term treatment because these agents can impair cognitive and psychomotor function, interact with various central nervous system depressants (eg, alcohol), and exhibit substantial potential for abuse, tolerance, dependence, and withdrawal effects. Buspirone and certain antidepressants, including the dual noradrenergic-serotonergic reuptake inhibitor venlafaxine, represent first-line therapy for GAD. Key words: generalized anxiety disorder, panic disorder, adjustment disorder, benzodiazepines, buspirone, antidepressants. (C/in Ther. 2000;22[Suppl A]:A3-A24) Accepted for publicatiof~ March 17, 2000. Printed in the USA. Reproduction

0149.2918/00/$19.00

in whole or part is not permitted.

A3

CLINICAL THERAPEUTICS”

INTRODUCTION Anxiety disorders are the most common form of mental illness in the United States and represent a formidable clinical challenge to the psychiatric community.’ Anxiety disorders are often missed because anxious patients typically present to primary care physicians with various somatic complaints that obscure the underlying psychiatric diagnosis.2 Nearly 30 million Americans with anxiety or depression present for treatment at some juncture in their lives.’ Approximately 20% to 40% of patients seen in general medical settings have significant anxiety or depression.36 Only about half of these psychiatric disorders are diagnosed, and a smaller proportion are treated adequately.5-7 Anxious patients rarely report psychological symptoms as a chief complaint because of the somatic nature of anxiety symptoms. In response to repeated visits, frustrated clinicians often institute costly diagnostic testing, treatment, and referrals. The attendant decline in costeffectiveness is particularly relevant in capitated reimbursement environments. Patients with untreated anxiety disorders consume a disproportionate share of health care resources. In 1990, costs associated with anxiety were $46.6 billion, which represented 31.5% of total expenditures for all treatment of mental illness and 47.3% of all indirect mental illness costs (including the costs of morbidity and mortality associated with anxiety disorders). The total costs associated with anxiety in 1990 were nearly 40% higher than corresponding costs in 1985.’ The effects of untreated anxiety on quality-of-life measures indicate that functional impairment approximates that seen in chronic medical conditions such

A4

as diabetes or congestive heart failure.8T9 Generalized anxiety disorder (GAD) is the most common anxiety disorder, with a lifetime prevalence of 5.1% in the adult US population.2 GAD predominantly affects women, and typically has a chronic course, with periodic exacerbation. This roundtable discussion will consider emerging diagnostic and clinical strategies in the management of GAD.

NATIONAL SURVEY

COMORBIDITY

The National Comorbidity Survey (NCS) demonstrated that nearly half (48%) of a US population sample of more than 8000 Americans aged 15 to 54 years had at least one mental illness in their lifetime.2 The age of onset of anxiety disorders peaks during the second and third decades, and the disorders affect women twice as often as men. Nearly one third (29.5%) had a psychiatric disorder in the 12 months preceding the survey (Table I). Approximately 1 of every 4 respondents (24.9%) reported having any anxiety disorder in their lifetime, and 17.2% reported having an anxiety disorder within the 12 months before the survey. Approximately 1 in 20 respondents (5.1%) reported ever having GAD, and 1 in 33 (3.1%) had GAD within the preceding 12 months. The NCS also documented that most of the burden of psychiatric morbidity is borne by 14% of the population. This group represented 59% of all mental disorders within the past 12 months and 89% of severe mental illness. This “high comorbidity” group had at least 3 diagnoses from the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R). Between 10% and 24% of respondents with psychiatric dis-

R.B. LYDIARD

Table I. Prevalence

of anxiety and other psychiatric

disorders. Prevalence

Disorder Any psychiatric disorder Any anxiety disorder Generalized anxiety disorder Panic disorder Any mood disorder Any substance abuse/dependence

disorder

(%)

Lifetime

12 Months Before Survey

48.0 24.9 5.1 3.5 19.3 26.6

29.5 17.2 3.1 2.3 11.3 11.3

From Kessler et al: with permission.

orders had been appropriately treated by mental health specialists. The NCS study data also suggest that preexisting anxiety may be a risk factor for depression. In -20% of individuals who experience concurrent anxiety and depression, anxiety preceded the onset of depression by -10 years. FEATURES OF GENERALIZED ANXIETY DISORDER GAD typically occurs before 40 years of age; runs a chronic, fluctuating course; and, as mentioned earlier, affects women twice as often as men.‘0*11 GAD confers functional disability at approximately the same level as depression.12 The criteria for GAD in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) require that patients exhibit at least 6 symptoms of motor tension, autonomic hypersensitivity, vigilance, or scanning (hyperarousal).” Several common somatic and psychological symptoms of GAD were reported in a recent study by Starcevic and Bogojevic.13 Because they were endorsed by

large proportions of GAD patients, 7 symptoms emerged in the first rank, including: (1) an inability to relax, restlessness, or a mentally tense or “keyed-up” state; (2) fatigability; (3) exaggerated startle response; (4) muscle tension; (5) sleep disturbance; (6) difficulty in concentrating; and (7) irritability. Second-rank symptoms consisted of: (1) nausea or abdominal complaints, (2) perspiring, (3) dry mouth, (4) tachycardia/palpitations, and (5) tremor.13 These investigators showed that the presence of at least 4 of 7 “firstrank” symptoms and 1 of 5 “second-rank symptoms” assisted in securing the diagnosis of comorbid GAD according to the Structured Clinical Interview for DSMIII-R modified for DSM-IV and Znternational Statistical Classification of Diseases, 10th Revision, Diagnostic Criteria for Research in 73 consecutive patients with panic disorder (PD)/agoraphobia. In a study by Marten et al,14 the 18 ratings that comprise the associated symptom criterion of DSM-III-R GAD were evaluated. For each of the 18 symptoms, the interrater reliability and endorsement rates were calculated using interview-

A5

CLINICAL THERAPEUTICS”

based ratings of patients with GAD at 4 study sites (N = 204). For most of the 18 symptoms, the interrater reliability analyses demonstrated high agreement. The frequency of symptom endorsement was assessed using Spearman correlations. Significant correlations (range, 0.69 to 0.94) revealed marked consistency in symptom endorsement rates across the 4 study sites. Seven “satisfactory” symptoms were identified from those meeting certain reliability and endorsement criteria: irritability, restlessness, muscle tension, difficulty concentrating, sleep difficulties, feeling keyed up, and easy fatigability. Of note, all these symptoms belong to either the motor tension or vigilance and scanning clusters of the DSMIll-R-associated symptom ratings. At all study sites, however, symptoms that belong to the autonomic hyperactivity cluster were endorsed infrequently. The authors concluded that these findings suggest that the associated symptom criterion of GAD should be revised in accordance with option E3 in the DSM-IV Options Book. In an article by Brawman-Mintzer et al,15 the distribution of somatic symptoms associated with GAD was compared in 28 patients with “pure” GAD and in 77 patients with GAD plus comorbid current or lifetime psychiatric diagnoses. No significant differences in individual symptom endorsement between the 2 groups were demonstrated. The authors concluded that the basic symptoms of GAD are disorder specific. Finally, Breitholtz and a group of cognitive behavioristsi recently demonstrated high diagnostic specificity of certain cognitions associated with distinct types of anxiety. These investigators used patient self-reports on the frequency of anxiety, worry, or panic attacks among patients with GAD (n = 38) and PD (n =

A6

36), as well as the severity of anxiety associated with each. Whereas 34% of GAD patients’ cognitions centered on interpersonal conflict or the issue of acceptance by others, only 1.4% of patients with PD reported such concerns. Patients with GAD also had exaggerated worries over relatively minor matters. On the other hand, PD patients had a significantly greater frequency of cognitions conceming physical dangers or catastrophes (eg, accident, injury, death). The Harvard Anxiety Disorder Research Project is a prospective, 1Zsite naturalistic study of 711 subjects with DSM-III-R anxiety disorders who have been followed up longitudinally for 6 to 9 years. Begun in 1989, it was undertaken to examine the course and comorbidity of the index anxiety disorders: GAD, PD with and without agoraphobia, and social phobia. l7 At the time of entry into the study, 179 patients had had GAD (median, 15.7 years); 82 patients had had PD with agoraphobia (median, 5.9 years); and 357 had had PD without agoraphobia (median, 12.9 years). The disabiity associated with GAD was similar to that found in PD or major depressive episode.

ANXIETY, SOMATIC COMPLAINTS, AND HEALTH CARE UTILIZATION The extent to which patients with psychiatic disorders have primarily physical complaints was documented by Bridges and Goldberg. 18 These investigators defined this masked presentation of psychiatric disorders - somatizationaccording to 4 operational criteria: the patient (1) had sought medical help for the somatic, rather than psychological, manifestations of mental illness (ie, “consulting behavior”); (2) had attributed the somatic symptoms to physical

R.B. LYDIARD

Table II. Mental health treatment

needs of distressed high utilizers (n = 119), % of Patients

Problem Unmet diagnostic needs Psychiatric diagnosis not made Psychiatric diagnosis incorrect Unmet treatment needs Tricyclic medications Inadequate tricyclic dosage

40.3

Mental health referral

31.1

Supportive therapy by physician

26.9

31.9 9.2 67.2 27.7 16.0

Total patients with unmet diagnostic and treatment needs

76.5

Patient-physician

42.8

relationship

diffkulties

Physician-patient conflict Patient noncompliance with medication

7.2 regimen

27.9

Axis II problem Adapted

with permission

11.7

from Katon et al. I9

causes; (3) met current criteria for a DSM111Axis I disorder; and (4) had presented with somatic complaints that responded to psychiatric treatment. In this study,‘* nearly 90% of 497 patients with psychiatric disorders had presented to primary care physicians with physical, rather than psychological, complaints. They detected a high rate of psychiatric disorders (94%) when the chief complaint was of a psychological or emotional nature, whereas psychiatric disorders in patients presenting with somatic complaints were detected in only half the cases. Patients who are the highest users of health care services also have high rates of psychiatric disorders. Among 767 patients in care utilization in a large health maintenance organization (HMO), more than half (51%) were identified as distressed according to scores on anxiety and depression scales (Table II).19 Katon et allSzl

reported that the members of a group health plan who represented the highest 10% of health care consumption could be characterized as “distressed” high health care utilizers by clinical rating scales, frequency of phone contacts, or being perceived as distressed by their physicians. This distressed high health care utilizer group accounted for approximately 50% of the total health care expenditures for that organization. The prevalence of GAD in this group was 39.5%; high rates of PD and depression were also found. Kroenke et al** recorded the presenting complaint in a large group of outpatients for a 3-year period. Figure 1 presents a range of physical complaints frequently associated with underlying anxiety disorders. A total of 35% of patients presenting with insomnia, for instance, were found to have anxiety disorders in a study of 1000 patients seen in primary care clinics.

A7

CLINICAL THERAPEUTICS’

Chest pain

Fatigue

Headache

Insomnia

Abdominal pain

Somatic Symptoms (N = 1000) Figure 1 Somatic symptoms as potential lected from patients presenting mission from Kroenke et alT2

DIAGNOSTIC ALGORITHMS: GENERALIZED ANXIETY DISORDER VERSUS PANIC VERSUS ADJUSTMENT DISORDER In light of the high prevalence, chronic@, and cost burden of untreated anxiety in primary care settings, better detection and treatment are clearly needed. Hales et a123 have formulated useful diagnostic and treatment algorithms for GAD. The diagnostic algorithm provides a differential diagnosis for anxiety that includes both medical and psychiatric conditions. Before establishing a diagnosis of GAD, the algorithms suggest ruling out medication side effects, medical illnesses, short-term psychiatric symptoms, acute adjustment reactions, and other primary anxiety disorders (GAD, PD, posttraumatic stress disorder, and obsessive-compulsive disorder) (Table III).”

A8

markers for anxiety disorders. Data were colat 4 primary care clinics. Modified with per-

As depicted in Figure 2, GAD is a chronic condition marked by a period of 26 months without an identifiable stressor.23 The hallmark feature of PD is al unexpected panic attack with 2 1 month of worry about further attacks with or without fearful avoidance (agoraphobia). Finally, acute anxiety that presents for only hours to weeks in the setting of a discrete, identifiable stressor is categorized as adjustment disorder with anxiety. 12*23,24 PD is characterized in the DSM-IV by an unexpected episode of intense fear or discomfort, with r4 symptoms from any of the following systems: cardiopulmonary, autonomic, gastrointestinal (GI), neurologic, or psychiatric. Cardiopulmonary symptoms of PD include angina or chest discomfort and perceived dyspnea or a sense of smothering, as well as palpitations, pounding heart, and/or tachycardia. Autonomic manifestations of PD

R.B. LYDIARD

Table III. Symptoms

of generalized

anxiety disorder.

Category

Distribution/Type

Somatic

Musculoskeletal

Symptom Restlessness or inability to relax Muscle aching or tension Easy fatigability

Gastrointestinal

Constipation/diarrhea Diffkulty

swallowing

(“lump in throat”)

Psychological

Excessive

Anxiety

worry and

anxiety that patient finds difficult to control Anticipation

of the worst

Fearful anticipation Irritability Sleep difficulties

Depressed symptoms Cognitive

Diffkulty

Other

Feelings of restlessness

concentrating

or jumpiness Adapted with permission from Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.”

are common and include sweating, chills, or hot flashes; GI symptoms include a sensation of choking, nausea, or abdominal distress.” Among the neurologic symptoms reported by patients with PD are tremor, paresthesias, dizziness, or a light-headed, unsteady, or faint feeling. Patients with PD exhibit typical cognitive and behavioral patterns. Catastrophic interpretation of symptoms (“I’m having a heart attack”) often lead to health care-seeking behavior and also avoidance of situations where an attack may occur. Adjustment disorder with anxiety, on the other hand, is typified by nervousness, worry, or jitteriness emerging within 3 months of the onset of identifiable stressors. Patients with anxiety secondary to

adjustment disorder suffer distress that is disproportionate to the stressors, and exhibit social, occupational, and academic impairment. *la TREATMENT ANXIETY

STRATEGIES

FOR

Patients with anxiety disorders should avoid stimulants, including coffee and other caffeinated beverages, and excessive intake of alcohol.25 Moderate exercise can assist in relieving tension and improving ~leep.*~ The primary care physician should monitor the use of over-the-counter medications that can precipitate or heighten anxiety, and seek to optimize patient compliance with pharmacologic regimens.25

A9

CLINICAL THERAPEUTICS”

Anxiety Symptoms (with or without panic attacks) 1

1

I

Panic Attacks (in addition to)

Acute Anxiety

Persistent Anxiety

Panic Disorder

Adjustment Disorder with Anxiety

Generalized Anxiety Disorder

Figure 2. Diagnostic algorithm for categorizing anxiety in primary care practice. Adapted with permission from Hales et a1.23

Psychosocial Treatments A broad spectrum of psychotherapeutic techniques is available for patients with GAD and other anxiety disorders. Cognitive-behavioral therapy (CBT) helps patients to self-monitor for excessive, unrealistic worry and to reassess their concerns more rationally. The aim of behavioral therapy, which is often effective in managing agoraphobia, is to use a combination of exposure and response prevention (eg, avoidance). Behavioral techniques include desensitization and in vivo exposure, both of which can assist in expanding the patient’s capacity to cope with or confront situations or objects associated with anxiety/panic attacks. CBT uses exposure to symptoms by inducing panic symptoms. For example, a patient may be asked to hyperventilate for 60 seconds to produce a dry mouth, light-headedness, paresthesias, and hot flashes. Alternatively, a patient may be asked to climb stairs to induce rapid breathing, heavy legs, and pounding heart. Other psychotherapeutic

A10

modalities include insight-oriented treatment and family or group therapy. Supportive therapy that allays fears, worry, and embarrassment about having a mental disorder, via patient education, can enhance patients’ coping skills. The physician should express willingness for the patient to discuss issues related to his or her anxiety. A thorough education of relevant treatment options supplemented with patient-oriented reading materials can confer hope and enhance the patient’s sense of control over the illness.

Pharmacotherapy of Generalized Anxiety Disorder, Panic Disorder, and Acute Adjustment Disorder Agents often recommended as first-line therapy for anxiety disorders include benzodiazepines for acute anxiety, buspirone or antidepressants for GAD, and antidepressants for PD (Figure 3).23 Because of their typically rapid onset of anxiolytic action, benzodiazepines are useful for acute anxiety and as an adjunctive treatment of

R.B. LYDIARD

Anxiety Symptoms (with or without panic attacks) 1 Panic Attacks (in addition to)

1 Acute Anxiety

t Persistent Anxiety Ei

Panic

Adiustment Disorder with Anxiety

Generalized Anxiety Disorder _

Educate and Support Figure 3. Treatment algorithm for the management of anxiety in primary care practice. CBT = cognitive-behavioral therapy. Adapted with permission from Hales et al.23

more chronic anxiety. However, the benzodiazepine agents are not recommended as first-line monotherapy for long-term management of anxiety disorders.23*26 Disadvantages of benzodiazepines include sedation, and, for some patients, problems with coordination initially; however, these problems generally resolve within the first few weeks of treatment. Other problems include complaints of memory difficulties and occasional emergent depression with long-term treatment.1,27 Another potential disadvantage of the benzodiazepines is that they may have additive effects with central nervous system (CNS) depressants, including alcoho1.28 Appropriate therapeutic use of the benzodiazepines is often limited by concern about physiologic dependence that occurs with long-term use. Another issue is con-

cern over the potential for abuse of benzodiazepines, even though empirical studies have shown that anxious patients abuse benzodiazepines at a very low rate.29 The antidepressant venlafaxine has been shown in placebo-controlled multicenter trials to be effective for the treatment of GAD, and has received approval from the US Food and Drug Administration for this indication.30 Other antidepressants, including imipramine and trazodone, have also been shown to be effective therapies for GAD.31,32 In a recent comparative study,33 paroxetine and imipramine were compared with the benzodiazepine 2’-chlordesmethyldiazepam, and all 3 treatments appeared to be effective. In this study, the benzodiazepine had an earlier onset of action, but by study end, all treatments were equally

All

CLINICAL THERAPEUTICS”

efficacious. Some open-label data for other antidepressants such as nefazodone suggest that it may also be an effective treatment for GAD, but further study is warranted.34 Wingerson et aP5 assessed the effects of the tricyclic antidepressant (TCA) clomipramine (50 to 250 mg/d) in 10 patients with GAD. Those who remained in treatment experienced significant improvement; because of intolerable side effects, only 5 patients completed the study. This report demonstrates the tolerability limitations due to side effects of the TCA when taken over the long term. Adverse effects of TCAs typically include anticholinergic effects (dry mouth, blurred vision, constipation), cardiovascular effects (orthostatic hypotension, slightly increased heart rate), sexual side effects, weight gain, and toxicity in overdose.36 Weight gain is also unfortunately common in long-term TCA treatment and can result in medication discontinuation. Activation may limit treatment in some patients, especially those with panic disorder and GAD. If these agents must be used, initiating treatment at a low dose and gradually titrating the dose upward to minimize treatment dropouts appears prudent.35 Bothersome short-term side effects of the newer antidepressants (venlafaxine and selective serotonin reuptake inhibitors [SSRIs]) occur in a significant number of patients; they include nausea, insomnia, jitteriness, restlessness, and agitation.30*36 However, by the initiation of treatment at doses approximately one half to one fourth of the usual recommended antidepressant dose, these side effects are generally manageable and time limited.30~36 Perhaps the most problematic side effect is the interference with sexual function (eg, delayed orgasm or abnormal ejaculation) in men

Al2

and women.36 Dose reduction can be sufficient in some cases but is often not an option. Pharmacologic agents that appear to be useful in counteracting SSRI sexual side effects include buspirone,37*38 dopamine agonists (bupropion, amantadine, methylphenidate),39 or sildenafil citrate.4o Some patients with poor initial response will benefit from a switch to a different SSRI or to an agent of a different class such as nefazodone. A smaller percentage of patients will experience SSRI-related somnolence or increased appetite with weight gain over the long term. 36 Finally, certain symptoms occur after discontinuation or rapid taper of the SSRIs. The most frequent symptoms are dizzinesslincoordination, headaches, nausea, and irritability, which typically resolve after several days or on reinstitution of the withdrawn agent.36,41 Buspirone, the only currently marketed azapemne, has been shown to be effective in the treatment of GAD, with anxiolytic efficacy comparable to that of the benzodiazepines.42 Although efficacy comparable to the benzodiazepines was initially demonstrated with relatively low doses of buspitone (5 mg TlD),% at least 30 to 60 mg/d is now considered a more standard therapeutic dose.36 Buspirone exerts anxiolytic effects via agonistic activity at presynaptic serotonin (ie, 5-hydroxytryptamine [5-HT,,]) receptors, presumably normalizing serotonergic transmission, and can exert partial agonist (or antagonist) activity at postsynaptic serotonin receptors.43 Like the antidepressants, buspirone displays a more gradual or progressive onset of action than the benzodiazepines. The progressive onset of buspirone’s anxiolytic efficacy was demonstrated by Feighner and Cohn4 in a pooled data analysis of patients treated with buspirone (10 to 60

R.B. LYDIARD

A

Fears Depressed mood Insomnia Intellectual Behavior Anxious mood Tension 0

1

2

3

4

3

4

Week B Genitourinary Muscular Gastrointestinal Respiratory Sensory Autonomic Cardiovascular 0

1

2

Week Figure 4. Significant between-group (buspirone vs placebo) differences in the Hamilton Anxiety Rating Scale for psychic (A) and somatic (B) symptoms. From Feighner and Cohr?’ with permission. mg/d) for 4 weeks. Compared with a control group (n = 225), patients randomly allocated to treatment with buspirone (n = 234) exhibited significant improvements in Hamilton Anxiety Rating Scale

(HAM-A) scores. Anxious mood, tension, and behavioral disturbance showed early improvement (week l), whereas other significant differences emerged from weeks 2 through 4 (Figure 4).

Al3

CLINICAL THERAPEUTICS”

01

0

I

I

1

I

r

I

1

2

3

4

5

6

Week

Figure 5. Mean Hamilton Anxiety Rating Scale (HAM-A) total scores at baseline and study weeks 1 through 6. *Significantly different from placebo (P < 0.05). Adapted with permission from Enkelmann.26

Buspirone treatment appears to be less effective in patients with a recent (<30day) history of regular benzodiazepine use but exhibits its usual therapeutic efficacy after benzodiazepine therapy has been stopped (~30 days). 45 Side effects most frequently reported by patients receiving buspirone include GI symptoms (appetite disturbances and abdominal complaints) and dizziness.& Buspirone does not exhibit cross-tolerance with benzodiazepines and will not block the withdrawal syndrome often associated with cessation of benzodiazepine therapy.47 These side effects could represent residual benzodiazepine withdrawal symptoms often seen with cessation of therapy with benzodiazepines. As noted earlier, various studies26,44*48 have demonstrated that buspirone has anxiolytic efficacy similar to that of the benzodiazepines and antidepressants. In one

Al4

placebo-controlled comparison,26 patients taking alprazolam (n = 94) showed comparable, clinically significant improvement in HAM-A ratings after 6 weeks of treatment (Figure 5). A blinded, comparative study48 of buspirone (n = 68) and diazepam (n = 71) in outpatients with GAD yielded comparable, clinically significant results for both agents. LONG-TERM TREATMENT OF GENERALIZED ANXIETY DISORDER Because GAD is a chronic condition, long-term treatment is often required. Most anxious patients experience a relapse after short-term treatment,49 while those treated for r6 months tend to exhibit a lower relapse rate than those treated for a shorter interval.45

R.B. LYDIARD

For chronic pharmacologic management of GAD and other persistent anxiety states, buspirone offers several advantages. Longterm buspirone therapy appears to be safe; no sedative effects or adverse effects on memory, cognitive function, or psychomotor performances were reported in a l-year study. 46 In addition, no abuse liability is associated with buspirone.47 Furthermore, dependence, acute withdrawal symptoms, and potentiation of CNS depressants are not clinical concems.47 Finally, buspirone has a favorable pharmacokinetic profile (eg, drug-drug interaction) and can be used safely with many commonly prescribed medications.47 Buspirone has been shown in vitro to be metabolized by cytochrome P-450 3A4 (CYP3A4); interaction has been observed with drugs that inhibit this isozyme (erythromycin, itraconazole, and nefazodone).47 Consequently, if buspirone is to be used in combination with a potent inhibitor of CYP3A4, a low dose of buspirone (eg, 2.5 mg BID) is recommended.47 Rake14’j conducted an open-label, longterm study of buspirone and noted that improvement of symptoms was maintained over a 1-year period. Mean decreases from baseline in HAM-A scores were 56.2% at 3 months (n = 167), 61.5% at 6 months (n = 167), and 68.5% at 12 months (n = 168) among patients who completed 1 year of buspirone treatment. For patients remaining on treatment, the physician and patient global ratings of much or very much improved were: at 3 months, physicians, 64%, and patients, 62%; at 6 months, physicians, 76%, and patients, 75%; and at 12 months, physicians, 85%, and patients, 80%. Although a clinical advantage of benzodiazepines is their relatively rapid onset of action, in more recent clinical practice, long-term treatment of GAD with nonbenzodiazepines is usually preferable. It has gener-

ally been assumed that long-ten-n GAD tmatment is similar to short-term treatment. Surprisingly, little is known about the long-term treatment of GAD. Rickels et alSo treated GAD patients with buspimne or the benzodiazepine clorazepate for 6 months and examined their status after the 6-month maintenance phase and again 4 weeks later. Both treatment groups remained well during the 6month maintenance phase, and no evidence of tolerance to or abuse of the benzodiazepine was observed. of interest, 4 weeks later, approximately one third of those treated with buspimne had moderate or greater anxiety rating, whereas 60% of the patients who had received clorazepate had significant anxiety. Despite initial efficacy of treatment, relapse rates for anxiety are substantial after relatively short-term (<6-month) treatment with diazepam or other anxiolytic medications.49y51 In one study,51 63% of patients completing a diazepam maintenance trial experienced a relapse of symptoms within a l-year follow-up interval; of these patients, nearly half (47%) relapsed within 3 months. Thus, many patients with GAD require pharmacologic management for years; for some patients, treatment may be required indefinitely. For those patients requiring long-term treatment, buspirone or antidepressants are the agents of choice. For some patients, buspirone may have advantages due to the lack of sexual side effects and absence of symptoms on abrupt discontinuation of antidepressants (venlafaxine, SSRIs, and the TCAs).

Practical Aspects of Switching Agents Some patients are intolerant to the initial antidepressant treatment or may express concern over the longterm treatment with benzodiazepines, and would

Al5

CLINICAL THERAPEUTICS”

like to explore alternative treatments of GAD. Still others who have been treated with benzodiazepines for acute stress disorder exhibit residual anxiety symptoms beyond 6 months. Some of these patients may benefit from CBT or other psychosocial treatments. If pharmacologic treatment with buspirone is indicated, a transition to long-term therapy with buspirone can be effected by first introducing buspirone at a dosage of 7.5 mg BID (5 mg BID for elderly patients) during week 1, when the patient is being treated with a benzodiazepine. At week 2, the buspirone dosage can be increased to 15 mg BID if well tolerated. Finally, the benzodiazepine dosage can be tapered beginning at week 3.43 For patients discontinuing benzodiazepines after short-term treatment (ie, 530 days), tapering can often be accomplished within a month. For patients who have taken benzodiazepines for several months or years, several months may be required for successful discontinuation. During the last 50% of the initial benzodiazepine dose, a slower taper is recommended after long-term benzodiazepine treatment. For patients receiving antidepressants, initiation of buspirone as described earlier, followed by a gradual taper of the antidepressant, is suggested.

CONCLUSIONS Patients with anxiety disorders frequently present to primary care physicians with somatic manifestations of their anxiety. For GAD, which tends to exhibit a chronic, relapsing course, buspirone and antidepressants are considered appropriate first-line pharmacologic treatment. Pharmacologic intervention should be instituted in conjunction with patient edu-

Al6

cation and support, keeping in mind that some patients will benefit significantly from CBT or other psychotherapy. GAD is a serious medical illness that may confer risk for additional psychiatric disorders, increased health care utilization, and functional disability. As such, every effort should be made to provide adequate treatment for the many patients who are “wartied sick.” Address correspondence to: R. Bruce Lydiard, PhD, MD, Director, Mood and Anxiety Program, Medical University of South Carolina, 67 President Street, PO Box 250861, Charleston, SC 29425.

REFERENCES 1. DuPont RL, Rice DP, Miller LS, et al. Economic costs of anxiety disorders. Anxiety. 1996;2: 167-172. 2. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51:8-19. 3. Barrett JE, Barrett JA, Oxman TE, Gerber PD. The prevalence of psychiatric disorders in a primary care practice. Arch Gen Psychiatry. 1988;45: 1100-l 106. 4. Burvill PW. The epidemiology of psychological disorders in general medical settings. In: Sartorius N, Goldberg D, de Girolamo G, et al, eds. Psychological Disorders in General Medical Settings. Lewiston, NY: Hogrefe & Huber Publishers; 1990:9-20. 5. Schulberg HC, Burns BJ. Mental disorders in primary care: Epidemiologic, di-

R.B. LYDIARD

agnostic, and treatment research directions. Gen Hasp Psychiatry. 1988;lO: 79-87. 6. Kamerow DB. Is screening for depression worthwhile in primary care? Screening criteria and the current state of depression research. In: Attkisson CC, Zich JM, eds. Depression in Primary Care: Screening and Detection. New York: Routledge; 1990:21-26. 7. Ormel J, Koeter MWJ, van den Brink W, van de Willige G. Recognition, management, and course of anxiety and depression in genera1 practice. Arch Gen Psychiatry. 1991;48:700-706. 8. Wells KB, Stewart A, Hays RD, et al. The functioning and well-being of depressed patients: Results from the Medical Outcomes Study. JAMA. 1989;262:914-919. 9. Fifer SK, Math& SD, Patrick DL, et al. Untreated anxiety among adult primary care patients in a health maintenance organization. Arch Gen Psychiatry. 1994; 5 1:740-750. 10. Walley El, Beebe DK, Clark JL. Management of common anxiety disorders. Am Fam Phys. 1994;50:1745-1753. 11. American Psychiatric Association. Anxiety disorders. In: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. DSM-lb! Washington, DC: American Psychiatric Association; 1994: 393-444. 12. Kessler RC, DuPont RL, Berglund P, Wittchen H-U. Impairment in pure and comorbid generalized anxiety disorder and major depression at 12 months in two national surveys. Am J Psychiatry. 1999; 156: 1915-1923.

13. Starcevic V, Bogojevic G. The concept of generalized anxiety disorder: Between the too narrow and too wide diagnostic criteria. Psychopathology. 1999;32:5-11. 14. Marten PA, Brown TA, Barlow DH, et al. Evaluation of the ratings comprising the associated symptom criterion of DSMIII-R generalized anxiety disorder. J Nerv Ment Dis. 1993;181:676-682. 15. Brawman-Mintzer 0, Lydiard RB, Crawford MM, et al. Somatic symptoms in generalized anxiety disorder with and without comorbid psychiatric disorders. Am J fsychiatry. 1994; 15 1:930-932. 16. Breitholtz E, Johansson B, Gst L-G. Cognitions in generalized anxiety disorder and panic disorder patients: A prospective approach. Behav Res Ther. 1999;37:533544. 17. Eisen JL. The impact of depression on the course of anxiety disorders. American Psychiatric Association 1999 Annual Meeting. Washington, DC; May 15-20, 1999. Washington, DC: American Psychiatric Association; 1999:243. Industry Symposium No. 19A. 18. Bridges KW, Goldberg DP Somatic presentation of DSM III psychiatric disorders in primary care. J Psychosom Res. 1985; 29:563-569. 19. Katon W, Von Korff M, Lin E, et al. Distressed high utilizers of medical care: DSM-III-R diagnoses and treatment needs. Gen Hosp Psychiatry. 1990;12:355-362. 20. Lin EHB, Katon W, Von Korff M, et al. Frustrating patients: Physician and patient perspectives among distressed high users of medical services. J Gen Intern Med. 1991;6:241-246.

Al7

CLINICAL THERAPEUTICS”

21. Katon W. Panic disorder: Relationship to high medical utilization, unexplained physical symptoms, and medical costs. J Clin Psychiatry 1996;57(Suppl 1O):l l-18. 22. Kroenke K, Spitzer RL, Williams JBW, et al. Physical symptoms in primary care: Predictors of psychiatric disorders and functional impairment. Arch Fam Med. 1994;3:774-779.

23. Hales RE, Hilty DA, Wise MG. A treatment algorithm for the management of anxiety in primary care practice. J Clin fsychiurry. 1997;58(Suppl 3):76-80.

24. American Psychiatric Association. Adjustment disorders. In: Diagnostic and Stutistical Manual of Mental Disorders, Fourth Edition. DSM-IK Washington, DC: American Psychiatric Association; lw623-627.

25. Carter C, Holloway R, Schwenk TL. Treating anxiety: A collaborative approach. Patient Care. November l&1994: 36-52.

26. Enkelmann R. Alprazolam versus buspirone in the treatment of outpatients with generalized anxiety disorder. Psychophurmacology. 1991;105:428432.

27. Lydiard RB, Laraia MT, Ballenger JC, Howell EF. Emergence of depressive symptoms in patients receiving alprazolam for panic disorder. Am J Psychiatry. 1987;144:664-665.

28. Ashton H. Toxicity and adverse consequences of benzodiazepine use. Psychiatr Ann. 1995;25:158-165.

29. Uhlenhuth EH, DeWit H, Balter MB, et al. Risks and benefits of long-term benzo-

A18

diazepine use. J Clin Psychopharmacol. 1988;8: 161-167. 30. Davidson JRT, DuPont RL, Hedges D, Haskins JT. Efficacy, safety, and tolerability of venlafaxine extended release and buspirone in outpatients with generalized anxiety disorder. J Clin Psychiatry. 1999; 60:528-535. 31. Hoehn-Saric R, McLeod DR, Zimmerli WD. Differential effects of alprazolam and imipramine in generalized anxiety disorder: Somatic versus psychic symptoms. J Clin Psychiatry. 1988;49:293-301. 32. Rickels K, Downing R, Schweizer E, Hassman H. Antidepressants for the treatment of generalized anxiety disorder: A placebo-controlled comparison of imipramine, trazodone, and diazepam. Arch Gen Psychiatry. 1993;50:884-895. 33. Rocca P, Fonzo V, Scotta M, et al. Paroxetine efficacy in the treatment of generalized anxiety disorder. Acta Psychiatr Stand. 1997;95:444-450. 34. Hedges DW, Reimherr FW, Strong RE, et al. An open trial of nefazodone in adult patients with generalized anxiety disorder. Psychopharmacol Bull. 1996;32:671-676. 35. Wingerson D, Nguyen C, Roy-Byrne PP. Clomipramine treatment for generalized anxiety disorder. J Clin Psychopharmacol. 1992;12:214-215. Letter. 36. Lydiard RB, Brawman-Mintzer 0, Ballenger JC. Recent developments in the psychopharmacology of anxiety disorders. J Consult Clin Psychol. 1996;64:660-668. 37. Land& M, Eriksson E, Agren H, FahlCn T. Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors. J Clin Psychopharmacol. 1999;19:268-271.

R.B.LYDIARD

38. Woodrum ST, Brown CS. Management of SSRI-induced sexual dysfunction. Ann Pharmacother. 1998;32:1209-1215. 39

40

Ellison JM. Antidepressant-induced sexual dysfunction: Review, classification, and suggestions for treatment. Harv Rev Psychiatry. 1998;6: 177-189. Rosenberg KI? Sildenafil citrate for SSRIinduced sexual side effects. Am J Psychiatry. 1999;156:157. Letter.

41. Haddad I? Newer antidepressants and the discontinuation syndrome. J Clin Psychiatry. 1997;58(Suppl 7): 17-22. 42. Rickels K, Schweizer E. The treatment of generalized anxiety disorder in patients with depressive symptomatology. J Clin Psychiatry. 1993;54(Suppl):20-23. 43. Cadieux RJ. Azapirones: An alternative to benzodiazepines for anxiety. Am Fam Phys. 1996;53:2349-2353. 44. Feighner JP, Cohn JB. Analysis of individual symptoms in generalized anxietya pooled, multistudy, double-blind evaluation of buspirone. Neuropsychobiology. 1989;21:124-130. E. The clinical 45. Rickels K, Schweizer course and long-term management of generalized anxiety disorder. J Clin PsychophurmacoZ.1990;10(Suppl):lOlS-110s.

46. Rake1 RE. Long-term buspirone therapy for chronic anxiety: A multicenter international study to determine safety. South Med J. 1990;83:194-198. 47. BuSpar@’(buspirone hydrochloride tablets, USP) prescribing information. Physicians’ Desk Reference. Available at: http://www. pdr.net/physician/psrec...&NS_template dir=&NS_initial_frm= 1. Accessed February 2,200O. 48. Rickels K, Weisman K, Norstad N, et al. Buspirone and diazepam in anxiety: A controlled study. J Clin Psychiatry. 1982; 43(12 set 2):81-86. 49. Rickels K, Case WG, Diamond L. Relapse after short-term drug therapy in neurotic outpatients. Int Pharmacopsychiatry. 1980;15:186-192. 50. Rickels K, Schweizer E, Csanolosi I, et al. Long-term treatment of anxiety and risk of withdrawal: Prospective comparison of clorazepate and buspirone. Arch Gen Psychiatry. 1988;45:444-450. 51

Rickels K, Case WG, Downing RW, Fridman R. One-year follow-up of anxious patients treated with diazepam. J Clin Psychopharmacol. 1986;6:32-36.

Al9

CLINICAL THERAPEUTICS@’

DISCUSSION: GENERALIZED ANXIETY DISORDER

Dr. Got-man: I find it interesting that about

Dr. Gorman: Another point regarding bu-

66% of patients with anxiety have already sought medical help for various complaints, and 40% have received treatment. Yet, you also stated that GAD is often not recognized or is undertreated. Those 2 premises are ostensibly contradictory. I think what happens is that, although patients with GAD have sought help and received treatment for various maladies, the diagnosis of GAD often has not been established. It may be more appropriate to say that GAD is mistreated or inaccurately treated rather than undertreated.

spirone is that, even in randomized clinical trials, the agent is often underdosed. In my clinical experience, 30 mg/d appears to represent a threshold dose for clinical response in anxiety disorders.

Dr. Sussman: In my judgment,

a variety of agents can be used in the treatment of GAD. There is a long history to suggest that TCAs and trazodone can improve anxiety disorders, and SSRIs probably exert some anxiolytic effects as well. When selecting a treatment for GAD, the question is, what are the trade-offs in terms of the patient’s quality of life? For instance, why would a clinician treat GAD with a drug that compromises sexual functioning or induces weight gain? Clearly, any treatment that spares these important considerations is preferable. One quality-of-life benefit with buspirone is that there is no psychomotor or cognitive interaction with alcohol. For patients who have an occasional cocktail or nightcap to blunt anxiety, buspirone is one of the few drugs for which there is no empirical basis to prohibit alcohol consumption.

A20

Dr. Rosenbaum: At higher doses, other favorable psychotropic benefits of buspirone are recruited, and the drug may begin to exert antidepressant effects. This issue points us in a different direction, namely, to the relationship between GAD and major depression. In about two thirds of patients, these 2 entities are comorbid. In family studies, relatives of patients with GAD are most likely to be diagnosed with depression, not PD or other disorders. Children at risk for depression tend to present in similar ways to children at risk for anxiety. Thus, developmentally, the premorbid or antecedent state for the development of both depression and anxiety is anxiety. Some people with anxiety continue with anxiety, whereas others, perhaps because of different environmental factors, develop depression. So it is difficult to establish whether anxiety is a risk factor for depression, antecedent of depression, or simply a somewhat disparate expression of the same diathesis.

Dr. Lydiard: When I talk to primary care physicians about GAD, I try to stress how it is often linked with depression. For instance, Breslau has reported that preexisting anxiety is a 2-fold-higher risk for de-

R.B. LYDIARD

pression in women compared with men. Women are twice as likely to have primary anxiety, and anxiety disorders elevate the risk of depression. This group showed that this risk factor (anxiety) may be one of the main reasons for the 2:l female-to-male ratio we see for major depression.

Dr. Rosenbaum: Are you suggesting that, in the absence of preexisting anxiety disorders, men and women have similar risks for developing depression?

Dr. Lydiard: That is what Breslau’s study suggests, yes. Because GAD leaves patients more prone to comorbid conditions such as depression-and the typical sequence is anxiety first, depression laterthere is a high premium on early recognition and treatment of GAD. Dr. Rosenbamn: So you are suggesting a strategy that discourages anxious patients from “grinning and bearing it,” but rather construing GAD as a carrier or risk state that should be treated vigorously. There is a similar model in use for contemporary treatment of patients at risk for psychosis. The lesson, then, would be to intervene early in persistent anxiety states to prevent anxiety from evolving into a chronic, highly comorbid condition such as depression.

Dr. Gorman: Weissman’s

longitudinal study of a depressed cohort is pertinent to this discussion. Dr. Weissman enrolled children with depression, followed up these children to adulthood, then followed up their children to adulthood-adult grandchildren of the original cohort with depression. She has observed that children who develop major depression almost always first present with GAD before reaching adulthood. These findings

support the concept of anxiety as a precursor state. The other important point for primary care physicians is that, although the lifetime risk for GAD is only about 5%, the risk of GAD in primary care clinics, among patients with routine medical problems such as hypertension or type 2 diabetes, is about 4 to 5 times higher than that in the general population. Finally, it is important to disabuse the myth that buspirone is ineffective in patients previously treated with benzodiazepines. Any such connection is highly dependent on the timing of benzodiazepine withdrawal and the administration of buspirone treatment.

Dr. Sussman: In the primary care setting, I think one of the major problems is differential diagnosis. Primary care physicians may struggle with several aspects of the GAD differential diagnosis, including PD, depression, and dysthymia. One factor that distinguishes patients with GAD from those with PD is the timing of the visit. Patients with PD tend to visit the clinician within days or even hours of an attack, whereas patients with GAD often exhibit long delays in seeking medical attention. People with GAD are often first advised of their need for treatment by a primary care physician. These chronic patients-rather than those with PD-are most likely to fare well on buspirone.

Dr. Rosenbaum: I would like to pose a question for the panelists: To what extent do you think chronic benzodiazepine use reflects the chronic@ of the disorder, and to what extent do you believe that people are merely treating their own discontinuation symptoms? Do you have a sense, from your clinical experience, that many GAD patients could carefully taper off A21

CLINICAL THERAPEUTICS”

point, it is difficult to wean GAD patients off benzodiazepines because they experience transient distress. Hence, it is virtually impossible to determine whether adverse consequences represent benzodiazepine-withdrawal phenomena or a reemergence of the persistent anxiety disorder.

tients coming off long-term benzodiazepines. One manifestation of anxiety seen in primary care that may actually be construed as a potential “cause” of GAD is irritable bowel syndrome [IBS], also termed spastic colon. The disorder is marked by abdominal pain with a change in bowel habits that is relieved by defecation and is seen frequently by primary care physicians. About 30% to 50% of patients with IBS also have GAD.

Dr. Rosenbaum:

Dr. Rosenbaum: Is there any relationship

benzodiazepines and fare no worse off these drugs than on?

Dr. Rothschild: From a practical stand-

Right. Primary care physicians might feel tom between 2 very strong competing arguments. One is that prolonged benzodiazepine use is generally not advisable. On the other hand, why should a clinician force an anxious patient who is doing well on treatment to stop that therapy? This can be a demoralizing problem.

Dr. Lydiard: Conscientious

primary care physicians might worry that they are encouraging or enabling substance abuse by treating a patient over the long term with a benzodiazepine. In reality, abuse of benzodiazepines by anxious patients very rarely occurs.

between symptomatic relief from GAD and improvement in bowel function? Are the 2 related?

Dr. Lydiard: If there is anxiety,

there appears to be a close association between relief of IBS and anxiety reduction. In almost all studies of anxious patients with GI symptoms-and even in some patients who do not appear to have psychiatric disorders-IBS improves with psychotropics, including anxiolytics and antidepressants.

Dr. Rosenbaum: Is there evidence, then, that these 2 conditions are etiologically linked or have a hereditary basis?

Dr. Sussman: I would argue that, in primary cam, the issue of tapering benzodiazepines should not be of great concern. Patients who continue to be distressed can have their benzodiazepine prescription refilled. Dr. Lydiardz Benzodiazepine discontinuation in both GAD and PD can be accomplished for most motivated patients provided that it is done slowly and carefully. This process can be facilitated through effective CBT that helps avoid overreaction to the return of some anxiety. Consultation with a specialist is often advisable for anxious pa-

A22

Dr. Lydiard: The 2 conditions tend to run in families. A recent monozygotic-twin study from Australia suggested that about 50% of IBS is genetic. The brain and the enteric nervous system [ENS] both come from the neural crest of the embryo and are morphologically distinct from all other nerves. This is why the ENS is often called “the little brain.” Dr. Rosenbaum:

Does IBS appear to transmit with the anxiety disorder, or is it just that one is a stressor for the other?

R.B. LYDIARD

Dr. Lydiird: In families of probands with IBS, first-degree relatives exhibited a higher degree of psychiatric disorders, not just IBS. But the study was small and may have “missed” the familial pattern that the Australian twin study strongly suggested. I and others have seen many pedigrees in which IBS appeared to run in the family.

Dr. Rosenbaum: Are there antecedents for IBS in childhood

Dr. Gorman: That is exactly right. Dr. Lydiard: I would not presume to second-guess Dr. Gershon. There is, however, substantial preclinical information that corticotropin-releasing factor mediates arousal-related GI motility. So there may be “indirect” connections of the CNS and ENS serotonin systems, at least theoretically.

as well?

Dr. Sussman: This discussion

Dr. Lydiard: It appears that children with recurrent abdominal pain tend to become adults with chronic abdominal pain or IBS and that they often have psychiatric comorbidity. Thus, recurrent bellyaches in children should raise one’s suspicion of GAD or other anxiety disorders.

Dr. Gorman: There is a fine book for the general audience-titled The Second Bruin-that addresses many of these issues. Written by Dr. Michael Gershon, this volume discusses the fact that the bowel has substantially more serotonin receptors than the brain. These are entirely separate receptor populations: there does not appear to be any relationship between brain serotonergic neurotransmission and bowel serotonergic neurotransmission. Both the ENS and the brain have common embryologic origins. In some cases of IBS, [psychiatrically] “lethal” quantities of serotonin are secreted into the vascular system by the gut.

Dr. Rosenbaum: It is usually assumed that the brain influences the intestinal tract, conveying a message of anxiety. Dr. Gershon appears to be implying that the converse may be true: that the gut also sends serotonergic signals to the brain, causing anxiety.

leads into the matter of the overall pathophysiology underlying GAD. Do we know of any other typical biologic processes associated with GAD?

Dr. Lydiard: The one consistent observation in this context is that patients with GAD have a relatively attenuated or blunted autonomic responsiveness to a range of emotional stressors. Increases in blood pressure and heart rate actually tend to be higher in nonanxious patients than in those with GAD. Mintzer and coworkers showed a typically constricted autonomic response to anxiogenic challenges. Dr. Treisman: Dr. Hoehn-Saric, one of my colleagues, has demonstrated the relationship to which Dr. Lydiard refers. The experimental paradigm involves placing patients in a galvanometer [or lie detector], then monitoring heart rate, blood pressure, and other variables before, during, and after an anxiogenic stimulus. NonGAD patients have a consistent increase in the galvanomic response to anxiety. On the other hand, patients with GAD exhibit responses of much smaller amplitude. Patients with GAD whose anxiety has been effectively treated show a trend toward normalization of autonomic responses, although these never reach normal levels. A23

CLINICAL THERAPEUTICS”

Dr. Lydiard: In the case of a patient with GAD and comorbid IBS, it is important to understand these and other relevant physiologic variables as well as the history of medication use, particularly if treatment with buspirone is contemplated. For what reason or diagnosis did the patient receive benzodiazepines in the first place? How soon after benzodiazepine treatment was buspirone initiated? Dr. Rosenbaum: Do you also wish to address the issue of effective buspirone dosage? Dr. Lydiard: If the patient received only 10 to 15 mg/d, as was believed to be the proper dose, it would be unreasonable to consider him or her a treatment failure. We now know that 30 mg/d appears to be the threshold at or above which more patients are likely to respond, whether buspirone is

A24

administered for primary treatment of GAD or as an augmentation agent. Finally, a minimum duration for a buspirone trial is about 4 to 6 weeks. If the agent is well tolerated and the patient has not responded after 4 weeks, the dosage should be increased and the patient’s progress reassessed after 2 to 3 more weeks.

BIBLIOGRAPHY Breslau N, Schultz L, Peterson E. Sex differences in depression: A role for preexisting anxiety. Psychiatry Res. 1995;58: 1-12. Gershon MD. The Second Brain. New York: Harper Collins; 1999. Warner V, Weissman MM, Mufson L, Wickamaratne PJ. Grandparents, parents, and grandchildren at high risk for depression: A three-generation study. J Am Acad Child Adolesc Psychiatry.

1999;38:289-296.