Does Prior Use of a Benzodiazepine Predict a Negative Response to Buspirone?
ABSTRACT & COMMENTARY
Source: DeMartinis N, et al. Prior benzodiazepine use and buspirone response in the treatment of generalized anxiety disorder. J Clin Psychiatry 2000;61:91-94.
Very little is known about predictors of positive or negative outcomes for anxiolytic treatments. It has been hypothesized that significant psychic anxiety predicts a response to serotonergic drugs and somatic anxiety predicts a response to benzodiazepines.1-2 In addition, a preliminary report suggested that prior treatment with a benzodiazepine might predict a reduced response to buspirone3 for several reasons: 1) patient perception that buspirone is ineffective (i.e., the former works fast, may induce a mild euphoria, and causes a potentially welcome sedation); 2) buspirone is initiated in the midst of withdrawal from the benzodiazepine; and 3) a selection bias (i.e., a patient who fails the benzodiazepine may be more likely to fail a subsequent treatment because of being treatment-resistant or -refractive).
DeMartinis and associates examined a large data set that consists of pooled results from all placebo-controlled studies for buspirone’s application for general anxiety disorder (GAD), including data on prior benzodiazepine use. They hypothesized that remote benzodiazepine use would have significantly less effect on the anxiolytic response of buspirone than recent benzodiazepine use, and that patients with no prior use would achieve the highest overall response to buspirone.
The data set included eight double-blind, placebo-controlled studies for patients diagnosed with GAD by semi-structured interviews. Each study used a one-week, single-blind placebo washout period before randomizing patients to four weeks of buspirone (< 30 mg/d), diazepam (< 30 mg/d), or placebo; the average dose of the drugs was 20 mg/d. Evaluations were done at weeks 1, 2, and 4 with the Hamilton Rating Scale for Anxiety. For the purposes of the analysis, patients were placed into one of three groups: 1) no prior benzodiazepine use within five years; 2) remote benzodiazepine use, defined as use discontinued more than one month prior to the study; and 3) recent benzodiazepine use, defined as within a month of the study. No baseline differences were found in terms of age, gender, and age of onset and severity of GAD for the buspirone, diazepam, or placebo groups. Buspirone patients in the recent benzodiazepine group dropped out of the study significantly more than those with remote benzodiazepine or no prior benzodiazepine groups (42% vs 21% vs 27%). No differences in attrition occurred between the recent, remote, and no prior benzodiazepine use for those randomized to the benzodiazepine or placebo groups. Buspirone patients in the recent benzodiazepine group also reported significantly more adverse events than those with remote benzodiazepine or no prior benzodiazepine use. Once again, the same was not true for those randomized to the benzodiazepine or placebo groups. Finally, buspirone patients in the recent benzodiazepine group had insignificant efficacy in terms of anxiety and overall clinical global improvement vs. placebo compared to those with remote benzodiazepine or no prior benzodiazepine use. Patients randomized to benzodiazepine did significantly better than placebo regardless of recent, remote, or no prior use of a benzodiazepine. Patients randomized to placebo did significantly poorer than the treatment groups (except for those on buspirone who had had recent benzodiazepine use). DeMartinis et al concluded that this study confirmed the hypothesis that recent benzodiazepine use negatively predicts outcome with buspirone for GAD. This retrospective study cannot rule out benzodiazepine withdrawal as a mediator of these results, but it can rule out the potential effect of initial treatment failure with a benzodiazepine as an indicator of a treatment-resistant or -refractive population, since they responded as well or better upon being randomized to a benzodiazepine in this study.
Comment by Donald M. Hilty, MD
There is no clear explanation for why recent benzodiazepine use negatively predicts outcome with buspirone for GAD. The drug’s mechanisms are distinct. It is possible that clinically obvious benzodiazepine withdrawal and/or subclinical withdrawal (if it exists, not discussed in the literature) increases anxiety and adverse events that are subsequently attributed to buspirone. The initiation of buspirone, or other nonbenzodiazepine anxiolytics following benzodiazepine use should be accompanied by patient education, and close clinical monitoring.
References
1. Rickels K, et al. Buspirone and diazepam in anxiety: A controlled study. J Clin Psychiatry 1982;43:81-86.
2. Rickels K, et al. Antidepressants for the treatment of generalized anxiety disorder: A placebo-controlled comparison of imipramine, trazodone, and diazepam. Arch Gen Psychiatry 1993;50:884-895.
3. Schweizer E, et al. Resistance to the anti-anxiety effect of buspirone in patients with a history of benzodiazepine use. N Engl J Med 1986;314:719-720.
Recent benzodiazepine use is a negative predictor for outcome for GAD patients subsequently given buspirone in terms of:
a. anxiety scores.
b. adverse events.
c. overall clinical global improvement.
d. All of the above
e. None of the above
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