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NEGATIVE AND FAILED CLINICAL TRIAL REPORTS
Key Words: anxiety, ␥-aminobutyric acid (GABA), panic disorder, selective GABA reuptake inhibitor, tiagabine
N o t F o r R e p r i n t
David V. Sheehan, MD, MBA, Kathy Harnett Sheehan, PhD, B. Ashok Raj, MD, and Juris Janavs, MD
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.
ABSTRACT ~ ␥-aminobutyric
An Open-Label Study of Tiagabine in Panic Disorder
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
32 • P SYCHOPHARMACOLOGY B ULLETIN : Vol. 40 · No. 3
5 However. these agents can take up to 3–6 weeks to achieve clinically meaningful responses. a selective GABA reuptake inhibitor (SGRI). 33 Sheehan.12 Tiagabine. benzodiazepines are often administered concurrently with an antidepressant to provide more rapid symptom relief.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.5 Indeed.11 However. including panic disorder.PB-40-3-05-Sheehan 11/14/07 5:36 PM Page 33 TIAGABINE IN PANIC DISORDER N o t F o r R e p r i n t METHODS Study Design and Patient Selection This was a 10-week.4. which enhance the effect of GABA via allosteric modulation of the GABAA receptor. and represents a potential target for therapeutic intervention. the quality of life in patients with panic disorder is comparable to that of patients with chronic medical conditions or depression.8. 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. increases synaptic GABA availability by selective inhibition of the GAT-1 GABA transporter.1. As many as 30% of patients become increasingly anxious during the first weeks of SSRI/SNRI therapy and discontinue medication.7.6 Those suffering from panic disorder are high utilizers of medical services. have well-documented anxiolytic activity9 and remain one of the most commonly prescribed medications for panic disorder.4 ␥-aminobutyric acid (GABA) has been implicated in the pathophysiology of anxiety disorders. 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. 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 Ն4 (rating of at least their psychiatric illness.13 Initial experience suggested that tiagabine may be effective in several anxiety disorders. open-label pilot study conducted at a single center in the United States. 3 . 40 · No. Harnett Sheehan and Raj P SYCHOPHARMACOLOGY B ULLETIN : Vol. over 50% of patients experience difficulty discontinuing benzodiazepine therapy.8 Benzodiazepines.5 In addition. 4 Between 30% and 80% of patients continue to experience symptoms of panic up to 6 years after initiating therapy.10 As a result of their rapid onset of action. including panic.
and substance abuse. taken in the morning with food. Study Assessments The primary efficacy measure was the clinician rated Sheehan Panic Disorder Scale (SPS). Adverse events were classified according to the COSTART definitions.PB-40-3-05-Sheehan 11/14/07 5:36 PM Page 34 TIAGABINE IN PANIC DISORDER Sheehan. hypersensitivity to tiagabine or its use within 6 months prior to the study or use at doses Ͼ8 mg/day at any time. the Hamilton Rating Scale for Anxiety (HAM-A). 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. receipt of electroconvulsive therapy within 6 months prior to the study. the 21-point Patient Global Improvement Scale (PGI-21). Two-sided P values less than 0. psychotherapy. . All scales were administered at baseline and weekly thereafter. 3 “moderately ill”) were enrolled into the study. 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). 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. and the Sheehan Disability Scale (SDS). Harnett Sheehan and Raj N o t F o r R e p r i n t 34 P SYCHOPHARMACOLOGY B ULLETIN : Vol. All patients provided written informed consent to participate. All patients who received at least one dose of tiagabine were included in the safety analyses. All patients received tiagabine. pregnancy or lactation. significant risk of suicide (as determined by the Mini International Neuropsychiatric Interview). or drugs with psychotropic effects.05 were considered significant. the 21-point Clinician Global Improvement Scale (CGI-21). Adverse events and vital signs were monitored at each study visit. the Panic Disorder Severity Scale (PDSS). the Panic and Anticipatory Anxiety Scale (PAAS). the Bandelow Panic and Agoraphobia Scale (PAS). use of other psychotropic medications. Dosing was initiated at 2 mg/day. corrections for multiple comparisons were not made. Since this was a pilot study. 40 · No. 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. Secondary measures included the patient rated SPS. Exclusion criteria included: history or presence of any other clinically significant psychiatric or general medical condition.
3 .01 versus baseline Sheehan.05 versus baseline **p Ͻ 0.PB-40-3-05-Sheehan 11/14/07 5:36 PM Page 35 TIAGABINE IN PANIC DISORDER RESULTS Patients Twenty-eight patients (23 females and 5 males) entered this open label study.9] years and the mean [SD] duration of panic disorder was 10. the mean total SPS showed reductions (improvements) of 21. N o t F o r R e p r i n t Outcomes At baseline the mean [SD] clinician rated SPS total score was 47. 3. the mean LOCF dose of tiagabine was 15. Medication Dose At the final visit. P SYCHOPHARMACOLOGY B ULLETIN : Vol. Of the 12 patients who discontinued. No.5 [13. Vol. Harnett Sheehan and Raj Psychopharmacology Bulletin. 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. FIGURE 1 35 Sheehan. one withdrew due to adverse events.6 . 2007. The mean [SD] age was 35.8] years.1 mg/day (range 4–20 mg/day). 40.7 [11.004) on the LOCF analysis. 40 · No.0 points (p Ͻ 0.8 points (p Ͻ 0. five due to lack of efficacy and six failed to return for further assessments. After 10 weeks of open-label tiagabine.03 level on the LOCF analysis at all weeks from week 3 through endpoint (Figure 1).003) on the observed cases analysis but only 12. The mean change from baseline on this scale was statistically significant at least at the p Ͻ 0. Harnett Sheehan and Raj CHANGE IN SHEEHAN PANIC DISORDER SCALE (PDS) – CLINICIAN RATED SCORE DURING 10 WEEKS OF OPEN-LABEL TIAGABINE (n ϭ 28) * p Ͻ 0.
P Ͻ 0. No.9 Ϯ 10. 2007.2 Ϯ 3. observed cases. 21-point Patient Global Improvement.8 4. OC. last observation carried forward.006 27.5.002 3.5.0 Ϯ 12.2. SPS.9 Ϯ 8.0006 6.004 1.8.9 24.0003 2.9. PAAS. P Ͻ 0. The SDS showed more of a lag with statistically significant improvement (p Ͻ 0.01) for the total SDS score at week 10.2 4.7 Ϯ 3.0 0 0 14.1 Ϯ 28.002 2.004 2. statistically significant reductions in social disability were observed from week 2 onwards and the mean change from baseline was significant (p Ͻ 0.003 40.04) on the total disability score not occurring until week 9. Harnett Sheehan and Raj Psychopharmacology Bulletin.3 Ϯ 3.0002 10.0 Ϯ 10. P Ͻ 0.2 Ϯ 1.8 Ϯ 18.003 50 19 31 35. 8. P Ͻ 0.7.7. P Ͻ 0. on the patient rated SPS from week 2 onwards.2.6 Ϯ 24.0 Ϯ 9. Overall. On this scale.2 Ϯ 3. P Ͻ 0. Harnett Sheehan and Raj N o t F o r R e p r i n t OUTCOME ASSESSMENT BASELINE MEAN WEEK 10 MEAN (OC) WEEK 10 MEAN (LOCF) 36 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 Ͼ2 47.4 Ϯ 18.001 3.1.8 Ϯ 3.7 Ϯ 3. P Ͻ 0.5 points for the PDSS (p Ͻ 0.5. P Ͻ 0.02 8. Panic and Anticipatory Anxiety Scale. mean improvements in total scores were 5.01 3.1. P Ͻ 0. P Ͻ 0.0008 4.4 Ϯ 5. and on the PDSS and PAS from week 3 onwards. LOCF.04 35 13 52 p-value versus baseline. Panic Disorder Severity Scale.8. Hamilton Rating Scale for Anxiety.4 26.3 Ϯ 3. At week 10.0 Ϯ 5. Bandelow Panic and Agoraphobia Scale.3 points for the PAS (p Ͻ 0.2 Ϯ 8. Sheehan Disability Scale.3. P Ͻ 0.1 0 20 80 25.003). P Ͻ 0.002 12.002).4.0. HAM-A.3 Ϯ 7. 21-point Clinician Global Improvement.8 16.1 Ϯ 7.05) over baseline was evident on the LOCF analyses of the total scores on the HAM-A from week 1 onwards.3 Ϯ 23. P SYCHOPHARMACOLOGY B ULLETIN : Vol.6. 40.04) at weeks 6 and 10 on the family disability subscale. and 4.003 19.009 18. P Ͻ 0.9 points for the HAM-A (p Ͻ 0. 3 . Vol. P Ͻ 0. P Ͻ 0.2 points for the patient rated SPS (p Ͻ 0.2. P Ͻ 0.9 Ϯ 2. on the LOCF analysis. P Ͻ 0. Sheehan.6 Ϯ 24. CGI-21. 4.7 Ϯ 7.3.001 2.04 11. statistically significant improvement (p Ͻ 0.6 Ϯ 3. 40 · No.9 Ϯ 7.9 Ϯ 3. PGI-21. P Ͻ 0. P Ͻ 0.7 points (p Ͻ 0.3 5. Similar reductions in anxiety symptoms and disability were observed over the 10-week period on the secondary efficacy measures (Table 1).6. 3.3 Ϯ 4.3 52.1. NS 3.7.. P Ͻ 0.4.0002 14. 12. no statistically significant change from baseline was detected on the work disability subscale. However. SDS. P Ͻ 0.PB-40-3-05-Sheehan 11/14/07 5:36 PM Page 36 TIAGABINE IN PANIC DISORDER TABLE 1 EFFECT OF TIAGABINE ON ASSESSMENT SCALE SCORES AFTER 10 WEEKS OF OPEN-LABEL TREATMENT IN PATIENTS WITH PANIC DISORDER (n ϭ 28) Sheehan.7 Ϯ 6. Sheehan Panic Disorder Scale. PDSS.04).009). PAS.
43%). drowsiness (n ϭ 7. dizziness (n ϭ 12. however. 11%) and sedation (n ϭ 12. 25%). 3 . 20% of patients had 1–2 panic attacks in the previous week and 80% had more than 2 attacks (median number ϭ 5). 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 As shown in Table 1 (LOCF data). Harnett Sheehan and Raj P SYCHOPHARMACOLOGY B ULLETIN : Vol. At endpoint. 43%). and 52% of patients experienced more than 2 attacks. 13% had 1-2 attacks. 11%). 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. 43%). complete metabolic panel or urinalysis between screening and study endpoint. 40 · No. 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). 37 Sheehan.002). CGI-21 scores improved by only 2.PB-40-3-05-Sheehan 11/14/07 5:36 PM Page 37 TIAGABINE IN PANIC DISORDER N o t F o r R e p r i n t Safety and Tolerability The most commonly reported adverse events (in Ն10% of patients) were nausea (n ϭ 12.0 points out of 10 (p Ͻ 0.16 and social anxiety disorder. headaches (n ϭ 12.001) over the 10-week period. Our findings are consistent with the adverse event profile observed in studies of tiagabine in other anxiety disorders including GAD. diarrhea (n ϭ 3. These AE’s were coded as possibly or probably related to treatment and they resolved when the dose was reduced. tiagabine has been associated with a potential risk of seizures in patients without a history of seizure disorder. DISCUSSION This open-label study investigated the efficacy and tolerability of tiagabine in patients with panic disorder. The majority of adverse events were mild or moderate in severity. Five patients dropped due to lack of efficacy. Overall. upper respiratory infection (n ϭ 6. headaches and facial muscle twitching).3 points out of 10 (p Ͻ 0. PGI-21 scores improved by 3.15 posttraumatic stress disorder.5. At baseline. Tiagabine was generally well tolerated with most adverse events being mild or moderate in severity and only one patient withdrawing due to adverse events. the percentage of patients experiencing panic attacks on the LOCF analysis of the PAAS was as follows: 35% had no attacks.18 The risk-benefit trade off is unfavorable for tiagabine in panic disorder.17 More recently. 21%). complete blood count. One patient experienced adverse events which were judged to be severe (dizziness. There were no significant changes in vital signs.
22 controlled release paroxetine. Although the changes in scores from baseline to week 10 were statistically significant. Two patients were followed for up to 5 months and reported further improvement in symptoms with continued treatment. a study has demonstrated that both paroxetine and sertraline had equivalent efficacy in panic disorder. PAS. randomized clinical trials include the SSRIs paroxetine.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.PB-40-3-05-Sheehan 11/14/07 5:36 PM Page 38 TIAGABINE IN PANIC DISORDER 38 Sheehan.e. Although tiagabine provided some improvement. 3 .21 In the current study. tiagabine was administered to four patients with DSM-IV panic disorder with or without agoraphobia. These reductions do not meet the commonly accepted definition for response i. because of several limitations.26 In addition. Coryell and Noyes found that one in four (25%) markedly improved. The findings reported here should. 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. almost 2/3 of the patients on tiagabine continued to have panic attacks at LOCF endpoint. three of the patients reported marked overall reduction of symptoms and were free from panic attacks. 63% of patients were panic-free by week 10 compared with 35% of patients who experienced no panic attacks following 10 weeks of tiagabine.14 After treatment with tiagabine 15 mg/day for up to 4 weeks. be interpreted with caution.25 and the SNRI extended release venlafaxine. 21 The results reported here are at variance with the findings of two reports.24 fluoxetine. the study had a small sample size and high patient discontinuation.8. In the study of controlled-release paroxetine.23 sertraline. The open-label nature of the study prevents a direct comparison of the effects of tiagabine with placebo or another comparator agent. however. Treatments currently approved for the treatment of panic disorder and shown to be significantly superior to placebo in double-blind. In addition. 40 · No. and SDS. 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. it was not statistically different from placebo. the results cannot be considered clinically significant. Moreover. although some contrasts can be made. the N o t F o r R e p r i n t P SYCHOPHARMACOLOGY B ULLETIN : Vol. Following paroxetine. a reduction from baseline of Ն50% or more. Harnett Sheehan and Raj GAD and PTSD.20 In a previous study of 43 patients with panic disorder or agoraphobia with panic attacks who took placebo for 8 weeks. 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.14 In one study.
Trends in recommendations for the pharmacotherapy of anxiety disorders. Are benzodiazepines still the medication of choice for patients with panic disorder with or without agoraphobia? Am J Psychiatry. This suggests that the outcomes for tiagabine may not be as clinically significant as those obtained with the SSRIs. Lanka GD. Am J Psychiatry. Harnett Sheehan and Raj P SYCHOPHARMACOLOGY B ULLETIN : Vol. International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications. Merikangas KR. and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Results from the National Comorbidity Survey. III. 11.9 at baseline to 19. Sharma SG. Depress Anxiety. Goisman RM. Prevalence. Work Group on Panic Disorder. Ondrasik J. 10. Selective GABAergic treatment for panic? Investigations in experimental panic induction and panic disorder. Otto MW. Lifetime and 12month prevalence of DSM-III-R psychiatric disorders in the United States. Ban TA. Frazer. J Clin Psychiatry. Yang K. severity. Safren SA. 39 Sheehan.PB-40-3-05-Sheehan 11/14/07 5:36 PM Page 39 TIAGABINE IN PANIC DISORDER N o t F o r R e p r i n t CONCLUSION The results from this small. McGonagle KA. 1998:271-286.160:1432-1438. Ulenhuth EH. Otto MW. REFERENCES 1.62:617-627. 8. Washington.66:1401-1408. Part 1: Tiagabine and other anticonvulsants with actions on GABA. Pollack MH. Chiu WT. Brown C. Benzodiazepines. Walters EE.60(Suppl 18):16-21. Nemeroff CB. 2nd ed. The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebocontrolled study. J Affect Disord. 5. Quality of life in patients with panic disorder.8 at week 10 (53% reduction from baseline). 20 One of the most commonly used criteria for the remission of panic disorder is the absence of panic attacks. 4. eds. USA. Arch Gen Psychiatry. Spencer M. Salzman C. Practice guideline for the treatment of patients with panic disorder. Machan JT. 6.51:8-19. Candilis PJ. Balter MB. 2002. Demler O.9. Rupprecht R. Ballenger JC. Achieving remission has emerged as an important goal in the treatment of psychiatric disorders. Simon NM. Eshleman S. 1992-1997. In: Schatzberg AF. whereas tiagabine resulted in a change from 24. 2003. Stahl SM. American Psychiatric Association. 1999. 1999. J Psychiatry Neurosci. 9. VI. Penava SJ. On this basis. Anticonvulsants as anxiolytics. et al. Kessler RC. J Clin Psychiatry. J Clin Psychiatry.155(Suppl 5):1-34. Pollack MH. 7. Nelson CB. and several criteria for remission of anxiety disorders have been proposed. Current concepts in the treatment of panic disorder. compared with only about one-third of patients receiving tiagabine in the current study. Manfro GG. approximately two-thirds of patients in the study of paroxetine achieved remission. 1998. ✤ ACKNOWLEDGMENTS This work was supported by Cephalon Inc. Van AM. Bruce SE.30:167-175. Textbook of Psychopharmacology.69:201-208.. 3 . Vasile RG. 2004. 1994. 2.0 at week 10 (24% reduction from baseline). J Nerv Ment Dis. 1999. Roy-Byrne PP. et al.187:429-434. 3. Snyder H. et al.9 at baseline to 9. 2005. 12.65:291-292. Hughes M. DC: American Psychiatric Press. PA. Zwanzger P.9:107-116. Zhao S. Longitudinal outcome with pharmacotherapy in a naturalistic study of panic disorder. HAM-A total score decreased from 20. Sheehan DV. Kessler RC. et al. 40 · No. McLean RY. 2005. Worthington JJ. open-label study suggest that the SGRI tiagabine may be of little benefit in patients with panic disorder. Arch Gen Psychiatry. 2005.
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