An Open-Label Study of Tiagabine in Panic Disorder - CiteSeerX

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NEGATIVE AND FAILED CLINICAL TRIAL REPORTS Key Words: anxiety, -aminobutyric acid (GABA), panic disorder, selective GABA reuptake inhibitor, tiagabine

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An Open-Label Study of Tiagabine in Panic Disorder

David V. Sheehan, MD, MBA, Kathy Harnett Sheehan, PhD, B. Ashok Raj, MD, and Juris Janavs, MD ABSTRACT ~ -aminobutyric

acid (GABA) has been implicated in the pathophysiology of anxiety disorders, including panic. Tiagabine, a selective GABA reuptake inhibitor (SGRI), has been shown to reduce symptoms of anxiety. This pilot study evaluated the efficacy and safety of tiagabine in patients with panic disorder. Male and female outpatients aged 18–64 years with a DSM-IV diagnosis of severe to moderately severe panic disorder (with or without agoraphobia) received open-label tiagabine 2-20 mg/day for 10 weeks. Outcome assessments included the Sheehan Panic Disorder Scale (SPS), Panic Disorder Severity Scale (PDSS), Bandelow Panic and Agoraphobia Scale (PAS), Hamilton Rating Scale for Anxiety (HAM-A), 21-point Clinician Global Improvement Scale (CGI-21), 21-point Patient Global Improvement (PGI-21) and the Sheehan Disability Scale (SDS). Scores were recorded at baseline and weekly intervals thereafter. Adverse events were monitored throughout the study. Of the 28 patients who enrolled in the study, 23 had one post-baseline visit and were available for LOCF outcome analysis. Although statistically significant reductions from baseline were observed for all of the outcome measures, the percentage improvements on individual scales were only in the 25-32% range which is not clinically significant. Tiagabine was generally well tolerated; the most common adverse events were nausea, dizziness and headaches. Only one patient discontinued tiagabine due to adverse events. These findings suggest that administration of tiagabine may be of little benefit in patients with panic disorder. Psychopharmacology Bulletin. 2007;40(3):32-40.

INTRODUCTION Panic disorder, characterized by the presence of recurrent unexpected attacks of anxiety accompanied by 4 or more somatic symptoms (palpitations, chest pain, nausea, trembling, dizziness)1 is common, with a 12-month and lifetime prevalence of approximately 2.7% and 3.5%, respectively.2,3 Patients with panic disorder suffer significant physical, mental, social and vocational dysfunction, while many patients indicate that their health and quality of life is diminished as a result of Dr. D. Sheehan, Dr. K. Sheehan, Dr. Raj and Dr. Janavs are affiliated with University of South Florida College of Medicine, Tampa, FL. To whom correspondence should be addressed: David V. Sheehan, MD, MBA, USF Institute for Research and Psychiatry, 3515 East Fletcher Avenue, Tampa, FL 33613, USA. E-mail: dsheehan@ health.usf.edu

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TIAGABINE IN PANIC DISORDER

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their psychiatric illness.4,5 Indeed, the quality of life in patients with panic disorder is comparable to that of patients with chronic medical conditions or depression.6 Those suffering from panic disorder are high utilizers of medical services. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for panic disorder because of their efficacy against a broad range of symptoms as well as common comorbid disorders.1,5 However, these agents can take up to 3–6 weeks to achieve clinically meaningful responses. As many as 30% of patients become increasingly anxious during the first weeks of SSRI/SNRI therapy and discontinue medication.4 -aminobutyric acid (GABA) has been implicated in the pathophysiology of anxiety disorders, including panic, and represents a potential target for therapeutic intervention.7,8 Benzodiazepines, which enhance the effect of GABA via allosteric modulation of the GABAA receptor, have well-documented anxiolytic activity9 and remain one of the most commonly prescribed medications for panic disorder.10 As a result of their rapid onset of action, benzodiazepines are often administered concurrently with an antidepressant to provide more rapid symptom relief.11 However, over 50% of patients experience difficulty discontinuing benzodiazepine therapy. 4 Between 30% and 80% of patients continue to experience symptoms of panic up to 6 years after initiating therapy.5 In addition, a naturalistic study demonstrated that nearly half of patients in remission and continuing to receive adequate antidepressant and/or benzodiazepine pharmacotherapy relapsed within 2 years of follow-up.12 Tiagabine, a selective GABA reuptake inhibitor (SGRI), increases synaptic GABA availability by selective inhibition of the GAT-1 GABA transporter.13 Initial experience suggested that tiagabine may be effective in several anxiety disorders, including panic disorder.8,14 The aim of the present study was to evaluate the short-term efficacy and safety of tiagabine in patients with panic disorder with or without agoraphobia.

33 Sheehan, Harnett Sheehan and Raj

METHODS

Study Design and Patient Selection This was a 10-week, open-label pilot study conducted at a single center in the United States. Male and female outpatients aged between 18 and 64 years with a DSM-IV diagnosis of moderate to moderately severe panic disorder (with or without agoraphobia)1 and a Clinical Global Impression-Severity (CGI-S) baseline score 4 (rating of at least P SYCHOPHARMACOLOGY B ULLETIN : Vol. 40 · No. 3

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“moderately ill”) were enrolled into the study. Exclusion criteria included: history or presence of any other clinically significant psychiatric or general medical condition; hypersensitivity to tiagabine or its use within 6 months prior to the study or use at doses 8 mg/day at any time; receipt of electroconvulsive therapy within 6 months prior to the study; use of other psychotropic medications, psychotherapy, or drugs with psychotropic effects; significant risk of suicide (as determined by the Mini International Neuropsychiatric Interview); pregnancy or lactation; and substance abuse. All patients received tiagabine. Dosing was initiated at 2 mg/day, taken in the morning with food. The dose was increased at the discretion of the clinician according to individual response and tolerability in increments of 2 mg every 3 days up to a maximum of 20 mg/day given in divided doses (with no more than 10 mg in a single administration). The protocol was approved by the Institutional Review Board prior to initiation and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. All patients provided written informed consent to participate.

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Study Assessments The primary efficacy measure was the clinician rated Sheehan Panic Disorder Scale (SPS). Secondary measures included the patient rated SPS, the Panic Disorder Severity Scale (PDSS), the Bandelow Panic and Agoraphobia Scale (PAS), the Hamilton Rating Scale for Anxiety (HAM-A), the Panic and Anticipatory Anxiety Scale (PAAS), the 21-point Clinician Global Improvement Scale (CGI-21), the 21-point Patient Global Improvement Scale (PGI-21), and the Sheehan Disability Scale (SDS). All scales were administered at baseline and weekly thereafter. Adverse events and vital signs were monitored at each study visit. Adverse events were classified according to the COSTART definitions. Statistical Analysis Paired t tests were used to evaluate the significance of change from baseline on the efficacy measures at each treatment visit and endpoint. Two datasets were used to analyze the efficacy results: an observed case (OC) dataset and a last observation carried forward (LOCF) dataset for patients who received at least one dose of tiagabine and had at least one post-baseline evaluation. Two-sided P values less than 0.05 were considered significant. Since this was a pilot study, corrections for multiple comparisons were not made. All patients who received at least one dose of tiagabine were included in the safety analyses.

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RESULTS

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Patients Twenty-eight patients (23 females and 5 males) entered this open label study. The mean [SD] age was 35.5 [13.9] years and the mean [SD] duration of panic disorder was 10.7 [11.8] years. Sixteen patients (57%) completed all 10 weeks of the study. Twenty-three (82%) had at least one post baseline visit and were available for the LOCF analysis. Of the 12 patients who discontinued, one withdrew due to adverse events, five due to lack of efficacy and six failed to return for further assessments. Medication Dose At the final visit, the mean LOCF dose of tiagabine was 15.1 mg/day (range 4–20 mg/day).

Outcomes At baseline the mean [SD] clinician rated SPS total score was 47.6 [20]. After 10 weeks of open-label tiagabine, the mean total SPS showed reductions (improvements) of 21.8 points (p 0.003) on the observed cases analysis but only 12.0 points (p 0.004) on the LOCF analysis. The mean change from baseline on this scale was statistically significant at least at the p 0.03 level on the LOCF analysis at all weeks from week 3 through endpoint (Figure 1).


FIGURE 1

CHANGE IN SHEEHAN PANIC DISORDER SCALE (PDS) – CLINICIAN RATED SCORE DURING 10 WEEKS OF OPEN-LABEL TIAGABINE (n 28)

* p 0.05 versus baseline **p 0.01 versus baseline Sheehan, Harnett Sheehan and Raj Psychopharmacology Bulletin. Vol. 40. No. 3. 2007.


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TABLE 1

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EFFECT OF TIAGABINE ON ASSESSMENT SCALE SCORES AFTER 10 WEEKS OF OPEN-LABEL TREATMENT IN PATIENTS WITH PANIC DISORDER (n 28) OUTCOME ASSESSMENT

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SPS-clinician rated SPS-patient rated PDSS PAS HAM-A CGI-21 PGI-21 SDS Total Work Social life Family life Panic attacks (PAAS) % with zero % with 1–2 % with 2

BASELINE MEAN

WEEK 10 MEAN (OC)

WEEK 10 MEAN (LOCF)

47.6 24.3 52.3 23.8 16.4 5.4 26.3 7.9 24.9 8.0 0 0

25.8 18.2; P 0.006 27.4 18.5; P 0.02 8.7 6.5; P 0.002 12.9 10.4; P 0.0002 14.2 8.0; P 0.002 3.9 3.7; P 0.0008 4.2 3.8; P 0.0006

35.6 24.5; P 0.003 40.1 28.1; P 0.04 11.9 7.7; P 0.009 18.0 12.4; P 0.003 19.0 10.1; P 0.002 2.3 4.2; P 0.001 3.0 5.7; P 0.0002

14.7 7.2 4.6 3.3 5.9 2.8 4.2 3.1

6.1 7.3; P 0.0003 2.3 3.3; P 0.004 2.7 3.2; P 0.004 1.2 1.6; P 0.003

10.0 9.8; P 0.01 3.3 3.9; NS 3.8 3.6; P 0.001 2.7 3.1; P 0.04

0 20 80

50 19 31

35 13 52

p-value versus baseline.; SPS, Sheehan Panic Disorder Scale; PDSS, Panic Disorder Severity Scale; PAS, Bandelow Panic and Agoraphobia Scale; HAM-A, Hamilton Rating Scale for Anxiety; CGI-21, 21-point Clinician Global Improvement; PGI-21, 21-point Patient Global Improvement; SDS, Sheehan Disability Scale; PAAS, Panic and Anticipatory Anxiety Scale; LOCF, last observation carried forward; OC, observed cases. Sheehan, Harnett Sheehan and Raj Psychopharmacology Bulletin. Vol. 40. No. 3. 2007.

Similar reductions in anxiety symptoms and disability were observed over the 10-week period on the secondary efficacy measures (Table 1). At week 10, on the LOCF analysis, mean improvements in total scores were 5.9 points for the HAM-A (p 0.002), 12.2 points for the patient rated SPS (p 0.04), 4.5 points for the PDSS (p 0.009), 8.3 points for the PAS (p 0.003). and 4.7 points (p 0.01) for the total SDS score at week 10. Overall, statistically significant improvement (p 0.05) over baseline was evident on the LOCF analyses of the total scores on the HAM-A from week 1 onwards, on the patient rated SPS from week 2 onwards, and on the PDSS and PAS from week 3 onwards. The SDS showed more of a lag with statistically significant improvement (p 0.04) on the total disability score not occurring until week 9. On this scale, no statistically significant change from baseline was detected on the work disability subscale. However, statistically significant reductions in social disability were observed from week 2 onwards and the mean change from baseline was significant (p 0.04) at weeks 6 and 10 on the family disability subscale.


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As shown in Table 1 (LOCF data), CGI-21 scores improved by only 2.3 points out of 10 (p 0.001) over the 10-week period, PGI-21 scores improved by 3.0 points out of 10 (p 0.002). At baseline, 20% of patients had 1–2 panic attacks in the previous week and 80% had more than 2 attacks (median number 5). At endpoint, the percentage of patients experiencing panic attacks on the LOCF analysis of the PAAS was as follows: 35% had no attacks, 13% had 1-2 attacks, and 52% of patients experienced more than 2 attacks. Safety and Tolerability The most commonly reported adverse events (in 10% of patients) were nausea (n 12; 43%), dizziness (n 12; 43%), headaches (n 12; 43%), drowsiness (n 7; 25%), upper respiratory infection (n 6; 21%), diarrhea (n 3; 11%) and sedation (n 12; 11%). The majority of adverse events were mild or moderate in severity. One patient experienced adverse events which were judged to be severe (dizziness, headaches and facial muscle twitching). These AE’s were coded as possibly or probably related to treatment and they resolved when the dose was reduced. Five patients dropped due to lack of efficacy. There were no significant changes in vital signs, complete blood count, complete metabolic panel or urinalysis between screening and study endpoint.


DISCUSSION This open-label study investigated the efficacy and tolerability of tiagabine in patients with panic disorder. Overall, the results indicated that tiagabine at a mean endpoint dose of 15 mg/day (in divided doses of 4–20 mg/day) reduced the symptoms of anxiety associated with panic disorder but not at a magnitude that was clinically meaningful. Tiagabine was generally well tolerated with most adverse events being mild or moderate in severity and only one patient withdrawing due to adverse events. Our findings are consistent with the adverse event profile observed in studies of tiagabine in other anxiety disorders including GAD,5,15 posttraumatic stress disorder,16 and social anxiety disorder.17 More recently, however, tiagabine has been associated with a potential risk of seizures in patients without a history of seizure disorder.18 The risk-benefit trade off is unfavorable for tiagabine in panic disorder, since the potential for increased risk of seizures outweighs the weak clinical efficacy (even if there is a statistically significant pre-treatment to posttreatment change). The results of this study are consistent with the findings from doubleblind placebo controlled studies in generalized anxiety disorder5 and posttraumatic stress disorder19 which have not supported the data from small open-label studies15-16 with respect to the efficacy of tiagabine in


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GAD and PTSD. Although tiagabine provided some improvement, it was not statistically different from placebo. The findings reported here should, however, be interpreted with caution, because of several limitations. The open-label nature of the study prevents a direct comparison of the effects of tiagabine with placebo or another comparator agent. In addition, the study had a small sample size and high patient discontinuation. Although the changes in scores from baseline to week 10 were statistically significant, the results cannot be considered clinically significant. Mean percentage reductions in the total scores at LOCF endpoint were no more than 25% on the HAM-A and the SPS (clinician and patient rated) and no more than 32% on the PDSS, PAS, and SDS. These reductions do not meet the commonly accepted definition for response i.e. a reduction from baseline of 50% or more.20 In a previous study of 43 patients with panic disorder or agoraphobia with panic attacks who took placebo for 8 weeks, Coryell and Noyes found that one in four (25%) markedly improved.21 In the current study, only 21% (5/23) of tiagabine treated patients had 50% or greater improvements on the clinician rated SPS and the HAM-A and only 26% (6/23) had 50% or greater improvement on the PDSS. Moreover, almost 2/3 of the patients on tiagabine continued to have panic attacks at LOCF endpoint. The tiagabine results in our own study are similar to those observed on placebo in the Coryell and Noyes study of placebo response in panic disorder. 21 The results reported here are at variance with the findings of two reports.8,14 In one study, tiagabine was administered to four patients with DSM-IV panic disorder with or without agoraphobia.14 After treatment with tiagabine 15 mg/day for up to 4 weeks, three of the patients reported marked overall reduction of symptoms and were free from panic attacks. Two patients were followed for up to 5 months and reported further improvement in symptoms with continued treatment. Treatments currently approved for the treatment of panic disorder and shown to be significantly superior to placebo in double-blind, randomized clinical trials include the SSRIs paroxetine,22 controlled release paroxetine,23 sertraline,24 fluoxetine,25 and the SNRI extended release venlafaxine.26 In addition, a study has demonstrated that both paroxetine and sertraline had equivalent efficacy in panic disorder.27 Differences in study design and outcome measures prevent direct comparisons between the results of the studies of the SSRIs and those of tiagabine reported here, although some contrasts can be made. In the study of controlled-release paroxetine, 63% of patients were panic-free by week 10 compared with 35% of patients who experienced no panic attacks following 10 weeks of tiagabine. Following paroxetine, the

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HAM-A total score decreased from 20.9 at baseline to 9.8 at week 10 (53% reduction from baseline), whereas tiagabine resulted in a change from 24.9 at baseline to 19.0 at week 10 (24% reduction from baseline). This suggests that the outcomes for tiagabine may not be as clinically significant as those obtained with the SSRIs. Achieving remission has emerged as an important goal in the treatment of psychiatric disorders, and several criteria for remission of anxiety disorders have been proposed.9, 20 One of the most commonly used criteria for the remission of panic disorder is the absence of panic attacks. On this basis, approximately two-thirds of patients in the study of paroxetine achieved remission, compared with only about one-third of patients receiving tiagabine in the current study. CONCLUSION The results from this small, open-label study suggest that the SGRI tiagabine may be of little benefit in patients with panic disorder. ✤ ACKNOWLEDGMENTS This work was supported by Cephalon Inc., Frazer, PA, USA.


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