Paroxetine Treatment of Generalized Anxiety Disorder: A Double-Blind ...

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Paroxetine Treatment of Generalized Anxiety Disorder: A Double-Blind, Placebo-Controlled Study Karl Rickels, M.D. Rocco Zaninelli, M.D. James McCafferty, B.S. Kevin Bellew, M.S. Malini Iyengar, Ph.D. David Sheehan, M.D., M.B.A.

Objective: This study assessed the efficacy of two fixed doses of paroxetine in the treatment of generalized anxiety disorder. Method: Outpatients (N=566) with generalized anxiety disorder and no other axis I disorder were eligible if they scored ≥20 on the Hamilton Rating Scale for Anxiety (with a score of 2 or higher on the anxious mood and tension items). Following a 1-week placebo run-in phase, patients were randomly assigned to 8 weeks of treatment with paroxetine, 20 or 40 mg/day, or placebo. The primary outcome measure was the change from baseline in total score on the Hamilton anxiety scale. Response was defined as a rating of “very much improved” or “much improved” on the Clinical Global Impression global improvement measure; remission was defined as a Hamilton anxiety scale score ≤7. Change in functional impairment was

measured with the Sheehan Disability Scale. Results: At 8 weeks, reductions in total score on the Hamilton anxiety scale were significantly greater for both paroxetine groups. Response was achieved by 62% and 68% of the patients receiving 20 and 40 mg of paroxetine, respectively, compared with a 46% response rate in the placebo group. Remission was achieved by 30% and 36% of patients in the 20and 40-mg paroxetine groups, respectively, compared with 20% given placebo. For all three domains of the Sheehan Disability Scale, significantly greater improvement was seen with paroxetine than placebo. Both doses of paroxetine were well tolerated. Conclusions: This study demonstrates that paroxetine is an efficacious and welltolerated treatment for generalized anxiety disorder. (Am J Psychiatry 2003; 160:749–756)

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eneralized anxiety disorder is characterized by excessive anxiety and worry about a number of everyday and routine events or activities such as work or academic performance. Afflicted persons find it difficult to control the worry and are restless, easily fatigued and irritable, and frequently complain of muscle tension and difficulty concentrating and sleeping. As defined by DSM-IV, the anxiety, worry, and physical symptoms are associated with significant subjective distress and impairment in social and occupational functioning. Generalized anxiety disorder is a common anxiety disorder in the United States, with a lifetime prevalence of 5.1% (1). According to an international multicenter study sponsored by the World Health Organization, generalized anxiety disorder is, after major depression, the second most frequent psychiatric disorder in the primary care setting (2), with approximately 8% of patients suffering from this illness (3). The course of generalized anxiety disorder tends to be chronic and recurrent (4), with less than one-half of cases remitting without treatment (5). Epidemiological research has also shown that the impairment caused by generalized anxiety disorder is equivalent in magnitude to that of major depression, with sufferers having a 2.5-times greater risk of social role impairment than healthy persons as measured by scales of social supAm J Psychiatry 160:4, April 2003

port and negative interaction with family and friends (6). Individuals with generalized anxiety disorder are high utilizers of medical care. At some point during their illness, 48% of generalized anxiety disorder patients seek professional help, and 25% of these patients require medication (7, 8). Benzodiazepines have traditionally been the mainstay in the pharmacotherapy of anxiety symptoms, and treatment trials demonstrate that this medication class is of benefit in treating generalized anxiety disorder (9, 10). Although effective in the short term, the benzodiazepines are associated with physical dependence, particularly with prolonged use (11). Current practice is therefore to restrict the use of these agents to less than 4 weeks (12), a period that may be insufficient for treating generalized anxiety disorder. Buspirone, a partial agonist at the 5-HT1A receptor, has also been studied as a treatment for generalized anxiety disorder. In studies with patients having symptoms corresponding to DSM-III generalized anxiety disorder, buspirone was shown to be effective (13). However, in a clinical trial assessing treatment of patients meeting DSM-IV criteria for generalized anxiety disorder, this medication failed to separate from placebo on several outcome measures (14). http://ajp.psychiatryonline.org

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PAROXETINE AND GENERALIZED ANXIETY DISORDER FIGURE 1. Trial Progression of Patients With Generalized Anxiety Disorder Randomly Assigned to 8 Weeks of Double-Blind Treatment With Paroxetine (20 or 40 mg/day) or Placebo

Eligible patientsa (N=661) Lost to follow-up (N=35) Adverse event (N=10) Protocol violation (N=6) Other (N=44b) Randomly assigned to treatment (N=566)

Placebo (N=180)

Paroxetine, 20 mg/day (N=189)


Withdrew because of adverse event before efficacy assessment (N=1) Evaluable for efficacy analysis (N=180)

Evaluable for efficacy analysis (N=188)

Evaluable for efficacy analysis (N=197)

Withdrawn (N=40) Adverse event (N=12) Lost to follow-up (N=8) Protocol deviation (N=9) Lack of efficacy (N=8) Other (N=3)



Completed trialc (N=140)



a Patients who signed an informed consent statement b Includes patients who withdrew consent. c All efficacy and safety assessments completed.

and had a prebaseline assessment.

TABLE 1. Demographic and Baseline Clinical Characteristics of Patients With Generalized Anxiety Disorder Randomly Assigned to 8 Weeks of Double-Blind Treatment With Paroxetine (20 or 40 mg/day) or Placebo Placebo Group (N=180) N %

Characteristic Gender Male Female Race African American Asian Hispanic White Other

Age (years) Age at onset of illness (years) Duration of illness (years) Hamilton anxiety scale scores Total Anxious mood item Tension item Psychic anxiety subscale Somatic anxiety subscale Hospital Anxiety and Depression Scale anxiety subscale score Clinical Global Impression severity of illness score Sheehan Disability Scale total score

750

http://ajp.psychiatryonline.org

20-mg Paroxetine Group (N=189) N %

40-mg Paroxetine Group (N=197) N %

79 101

44 56

87 102

46 54

87 110

44 56

10 3 11 147 9

6 2 6 82 5

9 5 10 155 10

5 3 5 82 5

7 2 5 175 8

4 1 3 89 4

Mean

SD

Mean

SD

Mean

SD

40.8 30.3 11.0

12.6 14.3 13.4

40.2 32.0 8.7

12.3 14.5 10.3

40.5 30.9 9.9

13.1 14.0 11.9

24.4 2.8 2.8 14.0 10.4 12.5 4.3 13.7

3.7 0.5 0.6 2.3 2.6 3.6 0.6 6.3

24.1 2.8 2.7 13.8 10.3 12.1 4.3 13.8

3.6 0.5 0.6 2.3 2.7 3.3 0.6 6.0

23.8 2.8 2.7 13.4 10.5 12.6 4.3 14.4

3.4 0.5 0.5 2.1 2.4 3.7 0.5 6.7

Am J Psychiatry 160:4, April 2003

RICKELS, ZANINELLI, McCAFFERTY, ET AL. FIGURE 2. Symptom Improvement in Patients With Generalized Anxiety Disorder Randomly Assigned to 8 Weeks of Double-Blind Treatment With Paroxetine (20 or 40 mg/ day) or Placebo

FIGURE 3. Functional Improvement in Patients With Generalized Anxiety Disorder Randomly Assigned to 8 Weeks of Double-Blind Treatment With Paroxetine (20 or 40 mg/ day) or Placebo Worka

0 Placebo (N=180) –2

Family Lifec

Paroxetine, 20 mg/day (N=188) Mean Change in Sheehan Disability Scale Subscale Score


–4 Mean Change in Hamilton Anxiety Scale Ratings Psychic Anxiety Subscale Score Total Score

Social Lifeb

0.0

–6 –8 –10 –12 –14

–0.5

–1.0

–1.5

–2.0

–2.5 Placebo (N=155)

0 –3.0 –1 –2

Paroxetine, 20 mg/day (N=164) Paroxetine, 40 mg/day (N=175)

Significant overall treatment effect (F=10.37, df=2, 443, p