- Email: [email protected]
The efficacy of sertraline in panic disorder: Dose—response relationships
$312
P.3 Anxiety disorders and anxiolytics
References [1] Olsen, R. W., McCabe, R. T., Wamsley,J. K., 1990. GABAAreceptor subtypes: autoradiographic comparison of GABA, benzodiazepine,and convulsant binding sites in the rat central nervous system. J. Chem. Neuroanat. 3, 59-76. [2] Liiddens, H., Pritcbett, D.B., Kiihler, M., et al., 1990. Cerebellar GABAA receptor selective for a behavioural alcohol antagonist. Nature 346, 648~i51.
~ T h e
efficacy of sertraline in panic disorder: dose-response relationships
J. Sheikh 1, R Londborg2, C. Clary 3. 1Stanford University School of Medicine, Department of Psychiatry and Behavioral Sciences, Stanford, CA 94305-5723; 2Seattle Clinical Research Center, Seattle, WA 98104; 3Pfizer Pharmaceuticals, New York, NY 10017, USA Objective: Sertraline has demonstrated efficacy in the treatment of panic disorder in daily doses ranging from 50-200 mg. To have sufficient power to assess whether there is a dose-response relationship for the efficacy and tolerability of sertraline in panic disorder, data from two fixed-dose studies were pooled and analyzed. Methods: The current investigation combined results from two identical 12-week studies. Male and non-fertile female patients were enrolled who met DSM-III-R criteria for moderate-to-severe panic disorder with or without agoraphobia. A minimal current panic attack frequency of 4 attacks in the previous 4 weeks was required, as well as three attacks during a 2-week single-blind pill placebo run-in period. At the end of the placebo run-in patients were randomized to double-blind treatment with either placebo, or one of three fixed daily doses of sertraline (50 mg, 100 mg, or 200 mg). Sertraline was initiated at 50 mg, then increased by 50 mg per week until the fixed dose level was achieved. Outcome was assessed by a conservative endpoint (LOCF) analysis of frequency of major or limited symptom panic attacks, change in panic burden (attack frequency X severity), and CGI-improvement. A subanalysis was performed to assess the effect on outcome of mild-to-moderate levels of subsyndromic depression (baseline HAM-D > 12 but _<17). Results: 82 patients were randomized to placebo (67% male; mean age, 38 yrs; 49% with agoraphobia; mean weekly panic attack frequency, 11.8); vs. 240 patients randomized to the three doses of sertraline (60% male, mean age, 40 yrs; 51% with agoraphobia; mean weekly panic attack frequency, 9.7). There were no significant differences in baseline values among the three sertraline dose levels. All 3 sertraline dose levels demonstrated significant efficacy compared to placebo, with no consistent evidence of a dose-response effect. For example, mean weekly panic attack frequency was reduced by -7.0 for 50 mg of sertraline (p = 0.012), -8.3 for 100 mg of sertraline (p = 0.001), and -6.8 for 200 mg of sertraline (p = 0.020), compared to -3.5 for placebo. For the subset of patients with subsyndromic depression at baseline, sertraline yielded a significantly higher panic-free rate (46%) compared to 24% for placebo (p = 0.021), again, by a conservative endpoint (LOCF) analysis. Similar results were found when responders were defined by an endpoint CGI of much or very much improved: 60% for sertraline vs. 38% for placebo (p = 0.020). There were no significant dose effects on responder rates using either criteria. Finally, sertraline was well-tolerated at all dose levels, with no significant between-dose differences in patients discontinuing due to adverse events. Results for additional outcome measures will be presented. Conclusions: 50 mg of sertraline demonstrated equivalent anti-panic efficacy to 100 mg and 200 mg doses. All doses were well-tolerated. The presence of mild-to-moderate subsyndromic levels of depression did not reduce the anti-panic efficacy of sertraline, nor did it necessitate use of higher doses. Research funded by Pfizer, Inc.
•
Measuring treatment outcome in patients with social anxiety disorder
S.A. Montgomery. Imperial College, University of London, UK Introduction: The Liebowitz Social Anxiety Scale (LSAS) has been used extensively as a primary outcome measure in social anxiety disorder pharmacotherapy trials. The magnitude of change from baseline in the LSAS total score which could be considered clinically relevant has not been previously published. Nevertheless, it is now possible to review the results across a range of pharmacotherapy trials including the recent results with paroxetine. Methods: 861 patients were recruited into three 12-week, multicentre, randomised, double-blind, placebo-controlled studies of paroxetine in the treatment of social anxiety disorder. Two of the three studies were flexible dose studies (paroxetine 20-50 mg/day) and the third was a fixed dose study (paroxetine 20, 40 or 60 mg/day). The mean change from baseline in the LSAS total score was a primary efficacy parameter in all three studies. Results: The LSAS total scores at baseline for the three study populations were in the range of 73 to 87; this represents severe social anxiety disorder. The changes observed from baseline LSAS total scores after 12 weeks' of paroxetine treatment (-30.5, -29.4, and -27.0 [combined paroxetine groups]) were approximately 14-15 points greater than those in the placebo groups and reflected a change from severe impairment to mild/moderate levels of impairment. The treatment differences between paroxetine and placebo were both statistically and clinically significant. The changes in LSAS total scores observed with paroxetine are greater than those reported in the recent moclobemide studies (International Multicenter Clinical Trial Group on Moclobemide in Social Phobia, 1997, Schneier et al 1998) and comparable with that seen in a recent phenelzine study (Liebowitz et al in press). Conclusions: Changes in the LSAS total score from baseline following paroxetine treatment reflect substantial clinical improvement.
References [1] International Multicenter Clinical Trial Group on Moclobemide in Social Phobia. Eur Arch Psychiatry Clin Neurosci 1997; 247:71-80 [2] Liebowitz et al. Arch Gen Psychiatry in press [3] Schneier et al. Br J Psychiatry 1998; 172:70-77
•
Response to paroxeUne is maintained during continued treatment in patients with social anxiety disorder
R. Kumar 1, C. Pitts2, D. Carpenter2. 1SmithKline Beecham Pharmaceu-
ticals, Harlow, Essex, UK 2SmithKline Beecham Pharmaceuticals, Collegeville, USA Introduction: The first large, randomised, placebo-controlled study of an SSRI in social anxiety disorder demonstrated short-term (12-week) efficacy of paroxetine for this severe and often disabling condition (Stein et al 1998). This long-term (24-week) extension investigates the effect of continued treatment. Methods: Patients who completed 12 weeks' treatment with paroxetine (20-50 mg/day) or placebo in the short-term study were eligible to enter a 24-week open-label phase with paroxetine followed by a 16week double-blind re-randomisation phase with paroxetine or placebo. The efficacy of further treatment was assessed using the Liebowitz Social Anxiety Scale (LSAS), Clinical Global Impression (CGI) Global Improvement Item, Social Avoidance and Distress Scale (SADS), and the Sbeehan Disability Scale (SDS; work, social and family life items). Results: Of the 90 patients who entered the open-label phase, the number of responders increased from 44/90 (44%) at the end of the 12week study to 57/64 (89%) after 24 weeks of paroxetine treatment. There was also a continuing improvement in LSAS scorns during the open-label phase and corresponding improvements in disability. Changes during the re-randomisation phase were also in favour of paroxetine treatment with
P.3 Anxiety disorders and anxiolytics
References [1] Olsen, R. W., McCabe, R. T., Wamsley,J. K., 1990. GABAAreceptor subtypes: autoradiographic comparison of GABA, benzodiazepine,and convulsant binding sites in the rat central nervous system. J. Chem. Neuroanat. 3, 59-76. [2] Liiddens, H., Pritcbett, D.B., Kiihler, M., et al., 1990. Cerebellar GABAA receptor selective for a behavioural alcohol antagonist. Nature 346, 648~i51.
~ T h e
efficacy of sertraline in panic disorder: dose-response relationships
J. Sheikh 1, R Londborg2, C. Clary 3. 1Stanford University School of Medicine, Department of Psychiatry and Behavioral Sciences, Stanford, CA 94305-5723; 2Seattle Clinical Research Center, Seattle, WA 98104; 3Pfizer Pharmaceuticals, New York, NY 10017, USA Objective: Sertraline has demonstrated efficacy in the treatment of panic disorder in daily doses ranging from 50-200 mg. To have sufficient power to assess whether there is a dose-response relationship for the efficacy and tolerability of sertraline in panic disorder, data from two fixed-dose studies were pooled and analyzed. Methods: The current investigation combined results from two identical 12-week studies. Male and non-fertile female patients were enrolled who met DSM-III-R criteria for moderate-to-severe panic disorder with or without agoraphobia. A minimal current panic attack frequency of 4 attacks in the previous 4 weeks was required, as well as three attacks during a 2-week single-blind pill placebo run-in period. At the end of the placebo run-in patients were randomized to double-blind treatment with either placebo, or one of three fixed daily doses of sertraline (50 mg, 100 mg, or 200 mg). Sertraline was initiated at 50 mg, then increased by 50 mg per week until the fixed dose level was achieved. Outcome was assessed by a conservative endpoint (LOCF) analysis of frequency of major or limited symptom panic attacks, change in panic burden (attack frequency X severity), and CGI-improvement. A subanalysis was performed to assess the effect on outcome of mild-to-moderate levels of subsyndromic depression (baseline HAM-D > 12 but _<17). Results: 82 patients were randomized to placebo (67% male; mean age, 38 yrs; 49% with agoraphobia; mean weekly panic attack frequency, 11.8); vs. 240 patients randomized to the three doses of sertraline (60% male, mean age, 40 yrs; 51% with agoraphobia; mean weekly panic attack frequency, 9.7). There were no significant differences in baseline values among the three sertraline dose levels. All 3 sertraline dose levels demonstrated significant efficacy compared to placebo, with no consistent evidence of a dose-response effect. For example, mean weekly panic attack frequency was reduced by -7.0 for 50 mg of sertraline (p = 0.012), -8.3 for 100 mg of sertraline (p = 0.001), and -6.8 for 200 mg of sertraline (p = 0.020), compared to -3.5 for placebo. For the subset of patients with subsyndromic depression at baseline, sertraline yielded a significantly higher panic-free rate (46%) compared to 24% for placebo (p = 0.021), again, by a conservative endpoint (LOCF) analysis. Similar results were found when responders were defined by an endpoint CGI of much or very much improved: 60% for sertraline vs. 38% for placebo (p = 0.020). There were no significant dose effects on responder rates using either criteria. Finally, sertraline was well-tolerated at all dose levels, with no significant between-dose differences in patients discontinuing due to adverse events. Results for additional outcome measures will be presented. Conclusions: 50 mg of sertraline demonstrated equivalent anti-panic efficacy to 100 mg and 200 mg doses. All doses were well-tolerated. The presence of mild-to-moderate subsyndromic levels of depression did not reduce the anti-panic efficacy of sertraline, nor did it necessitate use of higher doses. Research funded by Pfizer, Inc.
•
Measuring treatment outcome in patients with social anxiety disorder
S.A. Montgomery. Imperial College, University of London, UK Introduction: The Liebowitz Social Anxiety Scale (LSAS) has been used extensively as a primary outcome measure in social anxiety disorder pharmacotherapy trials. The magnitude of change from baseline in the LSAS total score which could be considered clinically relevant has not been previously published. Nevertheless, it is now possible to review the results across a range of pharmacotherapy trials including the recent results with paroxetine. Methods: 861 patients were recruited into three 12-week, multicentre, randomised, double-blind, placebo-controlled studies of paroxetine in the treatment of social anxiety disorder. Two of the three studies were flexible dose studies (paroxetine 20-50 mg/day) and the third was a fixed dose study (paroxetine 20, 40 or 60 mg/day). The mean change from baseline in the LSAS total score was a primary efficacy parameter in all three studies. Results: The LSAS total scores at baseline for the three study populations were in the range of 73 to 87; this represents severe social anxiety disorder. The changes observed from baseline LSAS total scores after 12 weeks' of paroxetine treatment (-30.5, -29.4, and -27.0 [combined paroxetine groups]) were approximately 14-15 points greater than those in the placebo groups and reflected a change from severe impairment to mild/moderate levels of impairment. The treatment differences between paroxetine and placebo were both statistically and clinically significant. The changes in LSAS total scores observed with paroxetine are greater than those reported in the recent moclobemide studies (International Multicenter Clinical Trial Group on Moclobemide in Social Phobia, 1997, Schneier et al 1998) and comparable with that seen in a recent phenelzine study (Liebowitz et al in press). Conclusions: Changes in the LSAS total score from baseline following paroxetine treatment reflect substantial clinical improvement.
References [1] International Multicenter Clinical Trial Group on Moclobemide in Social Phobia. Eur Arch Psychiatry Clin Neurosci 1997; 247:71-80 [2] Liebowitz et al. Arch Gen Psychiatry in press [3] Schneier et al. Br J Psychiatry 1998; 172:70-77
•
Response to paroxeUne is maintained during continued treatment in patients with social anxiety disorder
R. Kumar 1, C. Pitts2, D. Carpenter2. 1SmithKline Beecham Pharmaceu-
ticals, Harlow, Essex, UK 2SmithKline Beecham Pharmaceuticals, Collegeville, USA Introduction: The first large, randomised, placebo-controlled study of an SSRI in social anxiety disorder demonstrated short-term (12-week) efficacy of paroxetine for this severe and often disabling condition (Stein et al 1998). This long-term (24-week) extension investigates the effect of continued treatment. Methods: Patients who completed 12 weeks' treatment with paroxetine (20-50 mg/day) or placebo in the short-term study were eligible to enter a 24-week open-label phase with paroxetine followed by a 16week double-blind re-randomisation phase with paroxetine or placebo. The efficacy of further treatment was assessed using the Liebowitz Social Anxiety Scale (LSAS), Clinical Global Impression (CGI) Global Improvement Item, Social Avoidance and Distress Scale (SADS), and the Sbeehan Disability Scale (SDS; work, social and family life items). Results: Of the 90 patients who entered the open-label phase, the number of responders increased from 44/90 (44%) at the end of the 12week study to 57/64 (89%) after 24 weeks of paroxetine treatment. There was also a continuing improvement in LSAS scorns during the open-label phase and corresponding improvements in disability. Changes during the re-randomisation phase were also in favour of paroxetine treatment with