A Pilot Controlled Trial of Bupropion XL vs. Escitalopram in Generalized Anxiety Disorder (GAD)

Alexander Bystritsky, M.D.; Lauren Kerwin, B.A.; Jamie D. Feusner, M.D.; Tanya Vapnik, Ph.D.

Psychopharmacol Bull. 2008;41(1):1-9. 

Abstract and Introduction

Objective: To compare the efficacy and safety of bupropion XL (150-300mg/day) with the selective serotonin reuptake inhibitor escitalopram (10-20mg/day) in outpatients diagnosed with generalized anxiety disorder (GAD).
Methods: Twenty-four participants with GAD between the ages 18 and 64 years enrolled in a 12-week, double-blind, randomized, trial. The primary efficacy measures were the Clinical Global Impression of Improvement (CGI-I) and the Hamilton Anxiety Rating Scale (HARS).
Results: Bupropion XL demonstrated comparable anxiolytic efficacy to escitalopram in outpatients with GAD. Both treatments were well-tolerated.
Conclusion: Findings from this pilot project suggest bupropion XL may be useful in treating GAD. These preliminary results warrant further research to explore the use of bupropion XL in the treatment of GAD.

Generalized Anxiety Disorder (GAD) has a lifetime prevalence of 1.1% to 3.6%.1 Both cognitive behavioral therapies and medications have proved to be effective treatments.2 First line medication treatments are the serotonin reuptake inhibitors (SRIs) including escitalopram, which was approved by the FDA for the treatment of GAD in 2005.3 However, better-tolerated compounds are often needed, due to the fact that SRIs can cause problematic side effects such as sexual side effects.4 Support for the role of norepinephrine in the treatment of GAD comes from double-blind, placebo-controlled trials of tricyclic antidepressants (TCAs) that found them to be effective treatments for GAD.5

Bupropion hydrochloride, a norepinephrine and dopamine reuptake inhibitor (NDRI), has proven effective in clinical trials in major depressive disorder and has been an effective treatment for depression for over 20 years. Recent research suggests bupropion hydrochloride reduces anxiety in patients diagnosed with major depression.6, 7 Another study demonstrated that treatment with the sustained release (SR) formulation resulted in comparable anxiolytic efficacy to sertraline in outpatients with major depression.8 Moreover, both agents showed a rapid onset of clinically significant anxiolytic activity. The efficacy of bupropion and bupropion SR has also been demonstrated in patients with panic disorder and social phobia.9, 10

This pilot study explored the efficacy and safety of an extended release formulation of bupropion (bupropion XL) and the SRI escitalopram in outpatients diagnosed with GAD. Our primary hypothesis was that bupropion XL would demonstrate comparable anxiolytic efficacy to escitalopram in outpatients with GAD.

Methods

This study utilized a randomized, double-blind design to compare bupropion XL to escitalopram in the treatment of GAD. The study duration was 12 weeks and was conducted at the Pacific Institute for Medical Research from August 2004 to May 2005. All eligible subjects provided Western Institutional Review Board approved written consent prior to the initiation of any study-related procedures.

Subjects were randomly assigned by a computer program to either the bupropion XL (n = 11) or escitalopram (n= 13) treatment group. Bupropion XL was initiated at 150 mg/day and titrated after 2 weeks to a maximum daily dose of 300 mg/day. Escitalopram was initiated at 10 mg/day and titrated after 2 weeks to a maximum daily dose of 20 mg/day. Medication was provided by GlaxoSmithKline Pharmaceuticals.

The subjects of this study were a part of a larger study designed to explore the relationship between pharmacological intervention and measures of anxiety and resilience. Twenty four subjects (15=females, 9=males) with a primary DSM-IV diagnosis of GAD were included in the final analysis. The mean age of the sample was 35.04±9.55 (range, 21.3-64.3 years). Subjects needed a minimum score of 20 points on the Hamilton Anxiety Rating Scale (HARS) to participate and were excluded if their 21-Item Hamilton Depression Rating Scale (HDRS) was greater than 17.11, 12 Subjects were also excluded if they had a primary diagnosis meeting DSM-IV criteria for any Axis I disorder other than GAD, as were patients who met DSM-IV criteria for mental retardation, any pervasive developmental disorder or who had any neurological impairment. Also excluded were those with a current diagnosis or recent (6-month) history of drug or alcohol dependence, current suicidal ideation and/or history of suicide attempt, or personality disorder of sufficient severity to interfere with participation in the study.

At screening, psychiatric diagnosis was confirmed by the Mini International Neuropsychiatric Interview (MINI).13 Primary efficacy measures were the Clinical Global Impression of Improvement (CGI-I) and the HARS.14, 15 Secondary measures included the HDRS.16 Safety measures included physical examinations and routine laboratory tests before and after treatment, as well as vital signs collected at each of the visits. In addition, subjects were thoroughly questioned for adverse events in a general inquiry during all treatment visits.

Data were entered anonymously into a Microsoft Excel spreadsheet and analyzed by the UCLA Semel Institute Statistical Core after obtaining a UCLA IRB exemption. The analysis was done using the SPSS statistical package. One-way Analysis of Variance and Chi-square (non-parametric data) were employed to examine baseline demographic and clinical characteristics of the sample. Treatment effects were calculated by Analysis of Co-variance with baseline as a covariate. Statistical tests were two-tailed with α set at 0.05. The presence of clinically significant side effects was compared by Chi-square analysis between treatment groups.

Treatment response was defined as a reduction of 50% or more on the HARS and symptom remission was defined as a CGI-I score of 1 or 2 ("very much improved" or "much improved," respectively) and a score ≤ 8 on the HARS.

Results

Twenty four subjects received at least 1 dose of study drug and were included in the analysis (females=15, males=9). Eleven patients were randomized to the bupriopion XL treatment group (10=females, 1=male) and thirteen to the escitalopram treatment group (5 females, 8 males).

Baseline clinical and demographic characteristics were similar between the two treatment groups except for gender. The mean age of the sample was 35.04±9.55 years with no differences between the groups. The proportion of females in the bupropion XL group (91%, n=10) was significantly greater than the escitalopram group (38%, n= 5). Mean baseline HARS scores for the bupropion XL (N=11) and escitalopram (N= 13) groups were 25.8±15.09 and 26.15±2.99, respectively.

The mean daily dose of bupropion XL was 259.8±9.6 mg/day. Ninety percent (n=10) of patients received a dose of 300mg/day by week 12. The mean daily dose of escitalopram was 18.1±1.21. Ninety-two percent (n=12) of patients received a dose of 20mg/day by week 12.

Baseline and endpoint HARS and HRSD scores for both treatment groups are presented in . Both bupropion XL and escitalopram were associated with significant improvement in anxiety symptoms. Mean HARS scores at endpoint were 5.36±2.76 for bupropion XL and 11.38±6.57 for escitalopram. Mean changes from baseline were significantly greater for the bupropion XL-treated group than in the escitalopram-treated group at endpoint for the HARS total score (F= 8.30, dF=2,21, p<0.01).

  Outcome Measures by Treatment

  escitalopram
N=13
  bupropion XL
N=11
 
Measure Mean SD   Mean SD dF F* p
HARS Total Score Baseline 26.15 2.99   25.81 5.09 2, 21 8.30 0.01
HARS Total Score Endpoint 11.38 6.57   5.36 2.76
HRSD Total Score Baseline 13.30 3.72   13.54 2.84 2, 21 2.92 0.10 (ns)
HRSD Total Score Endpoint 8.76 5.21   5.63 3.29
Measure N %   N % dF X2 p
Responders 8 61.5   11 100 1,18 5.34 0.05
Remitters 6 46.15   8 72.73 1,13 1.73 0.20 (ns)

*ANCOVA with baseline as a covariate

Both bupropion XL and escitalopram were also associated with improvement in depressive symptoms, with endpoint HDRS scores of 5.63±3.29 and 8.76±5.21, respectively. However, the difference from baseline to endpoint between groups was not statistically significant.

The proportion of subjects who met criteria for treatment response was significantly higher in the bupropion XL-treated group (100%, n=11) than in the escitalopram-treated group (62%, n=8) (Χ² test, p=0.05) ( ).

  Outcome Measures by Treatment

  escitalopram
N=13
  bupropion XL
N=11
 
Measure Mean SD   Mean SD dF F* p
HARS Total Score Baseline 26.15 2.99   25.81 5.09 2, 21 8.30 0.01
HARS Total Score Endpoint 11.38 6.57   5.36 2.76
HRSD Total Score Baseline 13.30 3.72   13.54 2.84 2, 21 2.92 0.10 (ns)
HRSD Total Score Endpoint 8.76 5.21   5.63 3.29
Measure N %   N % dF X2 p
Responders 8 61.5   11 100 1,18 5.34 0.05
Remitters 6 46.15   8 72.73 1,13 1.73 0.20 (ns)

*ANCOVA with baseline as a covariate

A greater proportion of bupropion XL-treated subjects compared to escitalopram-treated subjects achieved remission at endpoint (73% vs. 46%, respectively). However this difference was not statistically significant.

Overall, 83% (n=20) of patients (82% of the bupropion XL and 85% of the escitalopram groups) completed the study. Both treatments were well tolerated and adverse events were comparable for bupropion XL and escitalopram, with the most common being insomnia (n=6 and n=1, respectively) and headaches (n=2 and n=4, respectively).

Discussion

Both treatments demonstrated anxiolytic efficacy in outpatients with GAD. There was a greater mean reduction in HARS for the bupropion XL relative to the escitalopram group. Response rates were significantly greater for bupropion XL (100%) than for escitalopram (62%). There was a non-significant trend for a greater proportion of bupropion XL-treated subjects compared to escitalopram-treated subjects achieving remission at endpoint (73% vs. 46%, respectively). Both treatments were well-tolerated.

These results agree with recent controlled and open trials, case reports, and animal studies which have identified decreases in anxiety levels during treatment with bupropion hydrochloride.17-19 To our knowledge, the use of bupropion XL in the treatment of GAD has not been previously studied. This is surprising, considering most treatments used to reduce symptoms of major depression also reduce symptoms of GAD.20-22 Clinicians may be hesitant to use bupropion due to past reports of the lack of efficacy and exacerbation of anxiety during treatment initiation in panic disorder patients.23 However, most antidepressants, including tricyclics and SRIs, also have activating effects during treatment initiation that eventually dissipate.24 In addition, the slowly releasing formulation of bupropion XL may be better tolerated in these regards than the faster releasing formulations used in previous studies.

This study has multiple methodological limitations that limit our ability to interpret the data. The study is limited by a small sample size, absence of placebo control, and a highly skewed percentage of males in the escitalopram group. Therefore, comparison of this work to other previously reported trials using different methodologies should be made with caution. It is clear that double-blind, placebo-controlled trials are needed to firmly establish the efficacy of bupropion XL for the treatment of GAD.

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