Levetiracetam in Generalized Social Anxiety Disorder: A Double-Blind, Randomized Controlled Trial
Objective: This multicenter, double-blind, placebo-controlled, 2-arm, parallel-group study was carried out to determine the effectiveness and safety of the novel anticonvulsant levetiracetam for the treatment of generalized social anxiety disorder (GSAD).
Method: After a 1-week, single-blind, placebo run-in period, 217 adult outpatients meeting DSM-IV criteria for social anxiety disorder, generalized type, were randomly assigned (1:1) to 12 weeks of double-blind treatment with either levetiracetam (n = 111) or placebo (n = 106). Participants were required to have scores of ≥ 60 on the Liebowitz Social Anxiety Scale (LSAS) and a total score of ≤ 17 on the 17-item Hamilton Depression Rating Scale (HDRS). The primary outcome measure was mean change from baseline on LSAS total score. Levetiracetam was initiated at 250 mg/d and flexibly titrated up to a maximum dose of 3,000 mg/d (1,500 mg bid). Dosage was held stable for the last 6 weeks of treatment. The study was conducted from September 2003 to June 2004.
Results: No statistically significant difference was found between the adjusted mean changes in LSAS score for levetiracetam (−24.4) and placebo (−28.7) using an efficacy intent-to-treat, last- observation-carried-forward analysis. Rates of response (≥ 30% reduction in LSAS score) were similar with 41.3% (levetiracetam) and 46.6% (placebo). No significant between-group differences were found on secondary outcome measures, which included changes in Sheehan Disability Scale, Clinical Global Impression of Change, and HDRS scores.
Conclusions: Although well-tolerated, levetiracetam failed to separate from placebo in this trial for the treatment of moderate to severe GSAD.
J Clin Psychiatry 2010;71(5):627–631
© Copyright 2009 Physicians Postgraduate Press, Inc.
Submitted: December 12, 2008; accepted February 2, 2009.
Online ahead of print: December 15, 2009 (doi:10.4088/JCP.08m04949gre).
Corresponding author: Murray B. Stein, MD, MPH, Anxiety and Traumatic Stress Disorders Research Program, University of California San Diego, 8939 Villa La Jolla Drive, Suite 200, La Jolla, CA 92037 ([email protected]).
With recent estimates of lifetime prevalence as high as 12.1%, social anxiety disorder (SAD) has been identified as one of the most common psychiatric conditions in the United States.1 Social anxiety disorder has also been shown to be associated with significant distress, impairment, economic burden, and elevated rates of comorbid disorders, so it is critical to provide early intervention, with available data supporting efficacy for both psychotherapeutic and psychopharmacologic approaches. While a number of effective medications, such as the serotonin reuptake inhibitors or the monoamine oxidase inhibitors, have demonstrated efficacy for SAD, response rates in clinical trials of these agents are limited to 40%-70% for acute treatment.2-4 Given these levels of nonresponse, it is important to develop novel agents for the treatment of SAD.
Pregabalin and gabapentin, each in 1 controlled study along with an open trial of topiramate, represent antiepileptic medications that have shown potential promise for the treatment of SAD.5-7 These studies have led to investigations of alternate anticonvulsant agents, such as levetiracetam, also for this purpose.
Levetiracetam has been approved by the US Food and Drug Administration for adjunctive treatment of certain kinds of epilepsy.8 It displays linear pharmacokinetics across the approved dose range and is rapidly absorbed. Levetiracetam is minimally protein bound, does not interact with the cytochrome P-450 system, and has few drug-drug interactions.9 While the exact mechanism by which levetiracetam may exert anxiolytic effects is unclear, levetiracetam has been shown to bind specifically to a unique binding site—the synaptic vesicle protein 2A. These proteins are thought to increase the probability of release of secretory vesicles into the synapse, thereby enhancing appropriate neurotransmission.10 This unique mechanism of levetiracetam is in contrast to the mechanisms of other anticonvulsant drugs.11,12
There is some preliminary clinical evidence to suggest potential efficacy of levetiracetam in the treatment of anxiety disorders. For example, a naturalistic study of 40 patients diagnosed with a DSM-IV anxiety disorder but with partial or nonresponse to standard treatment examined the effectiveness of adjunctive levetiracetam (250-3,000 mg daily).13 Following a mean (SD) duration of 9.3 (5.1) weeks of treatment, 48% of subjects were deemed responders. Similarly, a retrospective analysis of 23 patients with severe treatment-refractory posttraumatic stress disorder who were given a course of adjunctive levetiracetam along with their regular antidepressant reported significant improvements in all outcome measures, with 56% of patients eventually meeting responder criteria for the primary outcomes.14 Both studies noted that levetiracetam was well tolerated. Levetiracetam has also been investigated as a monotherapy agent for panic disorder.15 In this 12-week, open-label, flexible-dose study (N = 18), treatment with levetiracetam yielded a response rate of 67% in the intent-to-treat (ITT) population, with onset of clinical improvement evident even within the first 2 weeks. Again, the agent was well tolerated, with mild to moderate sedation the most frequently reported side effect.
Results from investigations of levetiracetam in SAD are mixed. Simon et al16 conducted an 8-week, open-label, flexible-dose study (N = 20) of individuals with generalized SAD. Patients experienced significant improvement in social anxiety symptoms, with few reported side effects. Analysis of completers in this study showed significant symptom improvement as early as the second week. A small 7-week, randomized, double-blind, placebo-controlled study was subsequently carried out by Zhang et al.17 In contrast to the other studies, no statistically significant differences were detected between placebo and levetiracetam treatment groups on primary outcome measures of social anxiety, although power was quite limited (N = 16). The authors noted a numerically greater reduction in social anxiety scores in the levetiracetam group and conducted a post hoc analysis that suggested that a larger trial of at least 62 patients per group might be sufficiently powered to demonstrate the efficacy of levetiracetam.
In order to resolve these conflicting findings and address some of the limitations raised by authors of these different trials, we conducted a well-powered 12-week, multicenter, randomized, double-blind, placebo-controlled, 2-arm, parallel-group study comparing levetiracetam and placebo as a treatment for SAD.
Method
This study was not registered with a clinical registry (eg, clinicaltrials.gov) as it was initiated in 2003, prior to the implementation of that requirement. From September 2003 to June 2004, 217 English-speaking, medically healthy outpatients, aged 18 to 70 years, with a clinically predominant diagnosis of DSM-IV social anxiety disorder, generalized subtype (GSAD), were recruited through advertisement and referral to be enrolled in this 12-week, randomized, double-blind, placebo-controlled study. The study was conducted in 20 centers across the United States with all procedures approved by the respective institutional review boards. All subjects were required to provide written informed consent after full explanation of the study and alternate treatment options.
Following the consent process, subjects were screened for study eligibility. The screening visit involved confirmation of GSAD diagnosis and evaluation of other psychiatric diagnoses with the Mini-International Neuropsychiatric Interview, a semistructured interview.18 In addition, medical history, physical exam including vital signs, and routine blood and urine tests were also conducted for safety monitoring and to ensure participants did not suffer from clinically significant medical conditions. Subjects were also required to have a score of ≥ 60 on the Liebowitz Social Anxiety Scale (LSAS)19 and a total score of ≤ 17 (with a score of ≤ 2 on the suicide subscale) on the 17-item Hamilton Depression Rating Scale (HDRS)20 to be included in the study. Female patients of childbearing potential were required to have a negative serum pregnancy test at screening and negative urine pregnancy tests administered periodically throughout the study. Other exclusion criteria included the presence of another primary Axis I disorder (including DSM-IV diagnosis of another anxiety, eating, or substance use disorder in the prior 6 months), failure to respond to adequate trials of ≥ 2 medications to treat GSAD, and concomitant psychotropic medications in the previous week (fluoxetine in the previous 4 weeks).
At the end of the screening visit, eligible subjects underwent a single-blind, 1-week, placebo lead-in period. Those who maintained an LSAS score ≥ 60 and a Clinical Global Impression of Change21 (CGI-C) > 2 (score range: 0-7) on their return visit (baseline—week 0) were then randomly assigned to double-blind treatment with either levetiracetam or matching placebo in a 1:1 ratio. Randomization was stratified according to LSAS scores at baseline (≤ 80, > 80) and age (≤ 40 years, > 40 years).
Study medication was titrated on a fixed schedule over the first 2 weeks from 250 mg/d up to 500 mg bid and then flexibly titrated over the next 4 weeks up to a maximum of 3,000 mg daily (1,500 mg bid). The dosage was then held stable for the remaining 6 weeks. Follow-up was weekly for 2 weeks and then at 2-week intervals until the end of the study (week 12).
The LSAS is a 24-item questionnaire assessing fear and avoidance of a range of social interactions and performance situations. All items are rated for both fear and avoidance, each scored on a scale of 0-3 (total score range: 0-144). The primary outcome for this study was change in total LSAS score from baseline to endpoint, with clinical response defined as ≥ 30% reduction of LSAS score from baseline and remission as an LSAS score ≤ 30 at the last evaluation visit attended. Secondary outcomes included CGI-C (response defined as final score of 1 or 2 [very much or much improved]) and changes in HDRS and Sheehan Disability Scale (SDS)22 over time.
Statistical Analyses
Sample size determination was based on detecting a 10-point mean treatment difference (estimated standard deviation [SD], 21.3) in the primary efficacy variable, change in total LSAS score. The presence of 95 evaluable patients in each treatment arm was calculated to provide 90% power for this difference, assuming a 2-sided, 2-sample independent group t test with a significance level of 5%. Assuming an attrition rate of 15%, we targeted a total of 224 patients for recruitment.
Analyses of results were performed for the efficacy ITT population (all randomized subjects who took any study medication and returned for ≥ 1 postbaseline evaluation) using the last observation carried forward (LOCF) as well as for observed cases completers analysis. Significance was examined using 2-sided hypothesis tests, with α = 5% for main effects and α = 10% for interaction effects. Changes in scores on primary outcome measure (LSAS) from baseline to last evaluation visit were compared using an analysis of covariance (ANCOVA), with treatment, pooled study center, and baseline LSAS scores in the model.
Results
Of 265 patients who were screened, 217 (n = 133 men) entered the randomization phase, with 111 assigned to levetiracetam treatment and 106 subjects assigned to placebo treatment. Reasons for failure to enter the randomization phase included ineligibility (n = 29), withdrawal of consent for personal reasons not related to adverse events (n = 7), other reasons (n = 6), lost to follow-up (n = 3), and adverse events during placebo lead-in phase (n = 3). One subject dropped out of the levetiracetam group prior to medication intake and so is not included in the analyses. Lifetime comorbid psychiatric diagnoses included depression (n = 24), panic disorder (n = 5), alcohol abuse (n = 3), and generalized anxiety disorder (n = 2). The mean ± SD age at illness onset was 14.0 ± 8.0 years, with duration of illness of 21.8 ± 13.4 years. The mean ± SD LSAS scores at baseline of 91.0 ± 18.1 for the levetiracetam group and 93.2 ± 19.4 for the placebo group were similar and indicated a population with moderate to severe GSAD. No statistically significant differences were found in baseline demographics or other measured clinical characteristics between treatment groups (Table 1).
Click figure to enlarge
Overall, 148 of the 217 randomly assigned patients (n = 77 [70%], levetiracetam; n = 71 [67%], placebo) completed the treatment period, with no statistically significant difference in attrition rates for each group. There were no differences in demographic or clinical characteristics of subjects who terminated the study prematurely. Reasons for early termination included adverse events (n = 11, levetiracetam; n = 6, placebo), lack/loss of efficacy (n = 5, levetiracetam; n = 4, placebo), withdrawal of consent not related to adverse events/lack of efficacy (n = 5, levetiracetam; n = 1, placebo), and other reasons (n = 7, levetiracetam; n = 5, placebo). A further 24 subjects were lost to follow-up (n = 5, levetiracetam; n = 19, placebo).
The mean ± SD daily dose of levetiracetam was 1,180 ± 780 mg compared to 1,250 ± 760 mg of placebo. Side effects were generally in the mild to moderate range of severity, with no statistical differences found in the rates of treatment-emergent adverse effects experienced by the 2 treatment groups. The most commonly reported side effects included headache (20%, levetiracetam; 27%, placebo), fatigue (14%, levetiracetam; 13%, placebo), and somnolence (16%, levetiracetam; 9%, placebo).
Click figure to enlarge
In the ITT sample, no statistically significant differences were observed between treatment groups at any time point on the primary outcome (change in LSAS total score) (Figure 1) or on any of the subscales of this measure. Rates of treatment response (≥ 30% reduction in total LSAS score) in the ITT sample were similar in both groups (41.3%, levetiracetam; 46.6%, placebo), and rates of remission (LSAS score ≤ 30 at endpoint) were also comparable (13.8%, levetiracetam; 18.4%, placebo). Similar findings were obtained with subsequent analysis of the observed cases completers-only subgroup. Results from the ANCOVA model were not clinically significant, revealing an adjusted mean difference (levetiracetam − placebo) in LSAS change scores of 4.3 (95% CI, −3.5 to 12.1; P = .282). Additional analyses of the primary outcome were performed on subgroups within the ITT population to determine possible predictors of response. Clinically significant treatment effects for levetiracetam were not detected in any of the subgroups, which were characterized by age, gender, race, baseline LSAS score, duration of illness, or presence of comorbid depression.
Likewise, analysis of secondary outcomes (HDRS, CGI-C [response defined as score ≤ 2], and SDS) did not reveal any between-group differences, regardless of whether the ITT or observed cases completers-only subgroup was used (Table 2).
Click figure to enlarge
Discussion
The results of this multicenter, randomized, double-blind, placebo-controlled clinical trial do not support levetiracetam as an efficacious monotherapy agent for SAD. While the mean decrease on the LSAS found with levetiracetam in this study was 25.4, which is comparable to the mean LSAS score changes found in other smaller studies of levetiracetam in SAD (ie, 20.5 and 28.7),16,17 it was not significantly different from that seen in the placebo-treated patients in this trial. Additional comparison of LSAS subscale scores failed to distinguish between treatment arms, and levetiracetam also produced similar results to placebo on all secondary measures.
The findings from this large, randomized controlled trial do not confirm the previous positive results from an open, uncontrolled report,16 but rather are consistent with the results from the earlier negative pilot placebo-controlled trial17 examining the use of levetiracetam for SAD and provides evidence—across multiple outcome measures—that levetiracetam was not an effective monotherapy treatment of GSAD. While we cannot exclude the possibility that levetiracetam might be a helpful medication for particular patients (eg, perhaps those with a comorbid seizure disorder and SAD) or that it may have a role as an adjunctive therapy to more standard agents, this study does not support its routine use for the treatment of GSAD.
Although levetiracetam may not be an effective treatment for people with SAD, it was safe and reasonably well tolerated in this study. Given the initial reports of its efficacy as monotherapy and an augmenting agent for panic disorder and posttraumatic stress disorder, respectively, it may still hold promise as a treatment of these other anxiety disorders. Hopefully, the investigation of other novel agents will prove more fruitful for the treatment of SAD.
Drug names: fluoxetine (Prozac and others), gabapentin (Neurontin and others), levetiracetam (Keppra), pregabalin (Lyrica), topiramate (Topamax).
Author affiliations: Anxiety and Traumatic Stress Disorders Research Program (Dr Stein) and Department of Psychiatry (Dr Ravindran), University of California, San Diego, La Jolla; Center for Anxiety and Traumatic Stress Disorder, Massachusetts General Hospital, and Department of Psychiatry, Harvard Medical School, Boston (Drs Simon and Pollack); Department of Psychiatry, New York State Psychiatric Institute, New York City, and Columbia University, New York (Dr Liebowitz); Department of Psychiatry, Northwest Clinical Research Center, Bellevue, Washington (Dr Khan); and Department of Psychiatry, Medical University of South Carolina (Dr Brawman-Mintzer), and Southeast Health Consultants, LLC (Dr Lydiard), Charleston, South Carolina.
Potential conflicts of interest: Dr Stein has received research support in the past 3 years from Eli Lilly and GlaxoSmithKline and has been a consultant for BrainCells, Bristol-Myers Squibb, Eli Lilly, EPI-Q, Forest, Hoffman-La Roche Pharmaceuticals, Integral Health Decisions, Jazz, Johnson & Johnson, Mindsite, Pfizer, Sanofi-Aventis, Sepracor, Transcept Pharmaceuticals, and Virtual Reality Medical Center. Dr Simon has received grant/research support from AstraZeneca, Bristol-Myers Squibb, Cephalon, Forest, GlaxoSmithKline, Janssen, Eli Lilly, NARSAD, National Institute of Mental Health (NIMH), Pfizer, UCB Pharma, and Sepracor; has served on advisory/consultation boards for American Foundation for Suicide Prevention, Paramount Biosciences, Pfizer, Sepracor, and Solvay; and has participated in speaking/CME activities for AstraZeneca, Forest, MGH Psychiatry Academy, Janssen, Eli Lilly, Pfizer, and UCB Pharma. Dr Liebowitz has been a consultant for AstraZeneca, Wyeth, Eli Lilly, Jazz, Tikvah, and Pherin; has served on the speakers/advisory boards for AstraZeneca, Wyeth, Bristol-Myers Squibb, and Jazz; has equity ownership in ChiMatrix LLC and Liebowitz Social Anxiety Scale (LSAS); has licensing software or LSAS with GlaxoSmithKline, Pfizer, Avera, Tikvah, Eli Lilly, Indevus, and Servier; and has had recent or has current clinical trial contracts with Pfizer, GlaxoSmithKline, AstraZeneca, Forest, Tikvah, Avera, Eli Lilly, Novartis, Sepracor, Horizon, Johnson & Johnson, Pherin, PGX Health, Abbott, Jazz, MAP, Takeda, Wyeth, and Cephalon. Dr Khan, principal investigator of over 330 clinical trials sponsored by over 55 pharmaceutical companies and 30 clinical research organizations, has done no compensated consulting or speaking on their behalf. Dr Brawman-Mintzer has been a consultant to and has served on speakers/advisory boards for Janssen and AstraZeneca; has received honoraria from AstraZeneca; and, more than twelve months ago, received grant/research support from Takeda, AstraZeneca, Bristol-Myers Squibb, Sanofi-Aventis, Novartis, Forest, Eli Lilly, and UCB.. Dr Brawman-Mintzer’s spouse, Dr Jacobo Mintzer, is the Director of the Division of Translational Research at the Medical University of South Carolina. He receives grant support from multiple pharmaceutical companies to perform double-blind, randomized clinical trials in Alzheimer’s disease. Dr Mintzer has not received any funding or support from UCB Pharma, maker of levetiracetam. Dr Mintzer is majority owner of a privately held company, BioPharma Connex. This company conducts business with pharmaceutical companies in the commercialization of different compounds in Latin America. None of the business of BioPharma Connex is related to UCB Pharma. Dr Lydiard has received grant/research support from Sanofi-Aventis, Eli Lilly, UCB Pharma, AstraZeneca, Wyeth, Bristol-Myers Squibb, and Forest and has served on speakers or advisory boards for Eli Lilly and Takeda. Dr Pollack has served on advisory boards for and provides consultation to AstraZeneca, BrainCells, Bristol-Myers Squibb, Cephalon, Dov Pharmaceuticals, Forest, GlaxoSmithKline, Janssen, Jazz, Labopharm, Eli Lilly, Medavante, Neurocrine, Neurogen, Novartis, Otsuka, Pfizer, Predix, Roche, Sanofi, Sepracor, Solvay, Tikvah Therapeutics, Transcept, UCB Pharma, and Wyeth; has received grant support from AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Forest, GlaxoSmithKline, Janssen, Eli Lilly, NARSAD, National Institute on Drug Abuse, NIMH, Pfizer, Roche, Sepracor, UCB Pharma, and Wyeth; has served on speakers boards for Bristol-Myers Squibb, Forest, GlaxoSmithKline, Janssen, Eli Lilly, Pfizer, Solvay, and Wyeth; has equity in Medavante and Mensante; and has received royalties/patents for the SIGH-A and SAFER. Dr Ravindran reports no financial or other relationships relevant to the subject of this article.
Funding/support: This study was funded in its entirety by UCB Pharma, USA.
Acknowledgment: The authors would like to thank all of the principal investigators who participated in this study: Richard Balon, MD, Department of Psychiatry, Wayne State University, Detroit, Michigan; Michael D. Banov, MD, Northwest Behavioral Medicine, Alpharetta, Georgia; Paul Bohn, MD, Department of Psychiatry, UCLA- Neuropsychiatric Institute, Los Angeles, California; Andrew Cutler, MD, University of Florida and Florida Clinical Research Center, LLC, Maitland; Lawrence Ginsberg, MD, Red Oak Psychiatry Associates, Houston, Texas; Richard G. Heimberg, PhD, Department of Psychology, Temple University, Philadelphia, Pennsylvania; James W. Jefferson, MD, Department of Psychiatry, Madison Institute of Medicine, Inc, University of Wisconsin School of Medicine and Public Health, Madison; Arifulla Khan, MD, Northwest Clinical Research Center, Bellevue, Washington; Michael R. Liebowitz, MD, PhD, The Medical Research Network, LLC, New York, New York; R. Bruce Lydiard, MD, PhD, Institute of Psychiatry, Medical University of South Carolina, Charleston; Olga Brawman-Mintzer, MD, Department of Psychiatry, Medical University of South Carolina, Charleston; Dennis J. Munjack, MD, Southwestern Research Inc, Burbank, California; Philip T. Ninan, MD, formerly of Emory University, Atlanta, Georgia; Mark H. Pollack, MD, Center for Anxiety and Traumatic Stress Disorders, Massachusetts General Hospital and Harvard Medical School, Boston; Norman Rosenthal, MD, Capital Clinic Research Associates, Rockville, Maryland; Franklin R. Schneier, MD, Anxiety Disorders Clinic, New York State Psychiatric Institute, New York; David Sheehan, MD, Department of Psychiatry and Behavioral Medicine, University of South Florida, Tampa; Mary Shemo, MD, Psychiatric Alliance Blue Ridge, Charlottesville, Virginia; Naomi M. Simon, MD, MSc, Center for Anxiety and Traumatic Stress Disorders, Massachusetts General Hospital and Harvard Medical School, Boston; Murray B. Stein, MD, MPH, Department of Psychiatry, University of California, San Diego, La Jolla; and Richard H. Weisler, MD, Department of Psychiatry and Behavioral Science, Duke University Medical Center, University of North Carolina at Chapel Hill, Raleigh.
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