Antidepressants for General Anxiety Disorder
November 15, 1999
Antidepressants for General Anxiety Disorder
Abstract & Commentary
Synopsis: This multicenter, randomized, double-blind, placebo-controlled study found the antidepressant venlafaxine (Effexor XR) to be effective, safe, and well-tolerated treatment for generalized anxiety disorder, even in the absence of depression.
Source: Davidson JRT, et al. J Clin Psychiatry 1999;60(8): 528-535.
This study compares venlafaxine (effexor xr) with buspirone (Buspar) and placebo in the treatment of general anxiety disorder (GAD) without comorbid major depression. Venlafaxine is believed to work by inhibiting both the serotonin and norepinephrine reuptake pumps. It is currently indicated for the treatment of depression. Buspirone is believed to work as an agonist of the presynaptic 5-HT1A autoreceptor (decreasing serotonin synthesis) and as a partial agonist at the postsynaptic 5-HT1A. Buspirone is currently indicated for the treatment of GAD. GAD has a lifetime prevalence of 5.1% and is associated with overuse of health care services, higher morbidity and mortality, and significant rates of psychiatric (e.g., depression) and medical (e.g., cardiovascular disease, irritable bowel syndrome) disorders.
Other options for the treatment of GAD have limitations. Benzodiazepines have a risk of dependence and a clinically significant withdrawal syndrome. Buspirone requires twice-daily dosing, which is less convenient for patients and potentially reduces adherence. In the current study, venlafaxine (75 mg/d vs 150 mg/d), buspirone 10 mg tid, and placebo were compared over an eight-week period. Final doses were reached within eight days of beginning the study. Assessment included the Hamilton Rating Scale for Anxiety (HAM-A), the Clinical Global Impression-Severity of Illness scale (CGI-S), and the Hospital Anxiety and Depression (HAD) anxiety subscale. Patients older than 18 years of age and those without major depression and panic disorder were included. The safety analysis included 405 patients and the clinical analysis included 365 patients. Overall HAM-A scores were lower for venlafaxine and buspirone but were not statistically different from placebo HAM-A. Psychic anxiety and tension scores were significantly improved in the venlafaxine group compared to the placebo group. CGI-S and HAD scores for venlafaxine were lower than for placebo and buspirone. Adverse events led to withdrawal from the study for 10% of the placebo group, 22% of the venlafaxine 75 mg/d group, 28% of the venlafaxine 150 mg/d group, and 15% of the buspirone group.
Nausea, dizziness, asthenia, and dry mouth occurred at rates of 15-34% with venlafaxine 75 mg/d, 21-44% with venlafaxine 150 mg/d, and 5-46% with buspirone. In summary, this study found venlafaxine to be effective, safe, and well-tolerated treatment for GAD, even in the absence of depression. Overall, venlafaxine was judged to be superior to placebo and comparable to, or slightly better than, buspirone. Once-daily administration is an advantage.
Comment by Donald M. Hilty, MD
Clinical experience has suggested that serotonergic antidepressants also are anxiolytics. However, this is the first double-blind, placebo-controlled efficacy trial. The fact that the patients did not have concurrent depression makes the finding even more important. Venlafaxine is mechanistically distinct from other antidepressants (inhibits both the serotonin and norepinephrine reuptake pumps) and, as such, the current findings cannot necessarily be extrapolated to other antidepressants.
There are a few caveats to consider about the study, and particularly the buspirone comparison. First, most physicians dose buspirone bid instead of tid, which probably does not affect efficacy but improves ease of use. Second, and more important, buspirone’s dose range of efficacy is from 15 mg/d to 60 mg/d, which may mean that patients were underdosed in this study. Third, seven patients on venlafaxine, seven on placebo, and two on buspirone received chloral hydrate, which may have influenced results. Fourth, the total HAM-A scores were not significantly different for venlafaxine, buspirone, and placebo. The studies leading to buspirone’s FDA approval for the treatment of generalized anxiety disorder did show statistically significant differences between buspirone and placebo in the psychic anxiety, somatic, and total HAM-A scores. In summary, more studies are necessary to provide additional data and to address the limitations and mixed results of this study. Venlafaxine is probably a reasonable choice for a patient with GAD. An antidepressant is a particularly good option in situations in which it may not be clear if the patient has generalized anxiety, depression, or both. At this point, though, it is premature to switch a patient doing well on buspirone to venlafaxine. (Dr. Hilty is Assistant Professor of Clinical Psychiatry, University of California, Davis, Sacramento, Calif.)
Which of the following medications treat both depression and generalized anxiety disorder?
a. Venlafaxine (Effexor XR)
b. Buspirone (Buspar)
c. Benzodiazapines
d. All of the above
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