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Pharmacological Treatments of Generalized Anxiety Disorder

For many years, benzodiazepines were the preferred pharmacotherapy for Generalized anxiety disorder and considered the treatment of choice. There is ample evidence to conclude that the benzodiazepines are safe and provide effective symptomatic relief for the majority of patients. Furthermore, numerous trials have shown that all benzodiazepine groups appear to be equally effective. In their meta-analytical study, Gould et al. (1997b) reported a mean anxiety effect size of 0.70 across 23 controlled trials of benzodiazepine therapy, equivalent to that calculated across all the “cognitive behavioral” therapies included in that study. While benzodiazepines undoubtedly produce good short-term treatment effects, side-effects include impaired cognitive performance, drowsiness and lethargy with high doses, and physical and psychological dependence following prolonged use. Discontinuation of benzodiazepine treatment can result in rebound anxiety or an intensification of previous symptoms in 25% to 75% of individuals, in a withdrawal syndrome in 40% to 100%, and a relapse of original symptoms in 63% to 81% of individuals. Few pharmacotherapy studies address long-term outcome, but in one study using DSM-III-diagnosed patients, discontinuation of diazepam (when provided as the sole treatment) resulted in a reversal of treatment effects. Although there is little research on long-term pharmacotherapy, some patients will have taken benzodiazepines for many years without tolerance to their anxiolytic effects. However, medical, ethical, and legal concerns surrounding the long-term use of these drugs, particularly in regard to the potential for dependence, have led to recommendations of intermittent usage, using the lowest effective dose for the shortest possible time. Gale and Oakley-Browne (2000) have concluded in their evidence-based review that, although benzodiazepines are, compared with placebo, an effective and rapid treatment for Generalized anxiety disorder, they are not a beneficial treatment because of the trade-off between benefits and harms. In particular, they state that benzodiazepines have been found to increase the risk of dependence, sedation, industrial accidents and road traffic accidents. Furthermore, benzodiazepines have been associated with neonatal and infant mortality when used in late pregnancy or while breastfeeding. Benzodiazepines should be used particularly cautiously in older adults because of the greater sensitivity to adverse effects.

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The nonbenzodiazepine anxiolytic buspirone appears to be equivalent to the benzodiazepines in efficacy but unlike the benzodiazepines produces virtually no sedative effects and no withdrawal syndrome or rebound anxiety following discontinuation. Gould et al. (1997b) reported a mean anxiety effect size of 0.39 from nine controlled trials of buspirone, apparently lower than that calculated from the benzodiazepine trials, but with equivalent dropout rates. Like the benzodiazepines, discontinuation of buspirone can lead to the return of original symptoms (Rickels and Schweizer, 1990). Its effects are likely to be mediated primarily through the dopaminergic neurotransmitter system, there is no cross-tolerance with benzodiazepines or alcohol, and the onset of anxiolytic effect may take several weeks. Some have suggested that buspirone may be useful for long-term use, given its lack of dependence potential, but its long-term effects are largely unknown.

Gale and Oakely-Browne (2000) have concluded that the antidepressants paroxetine, imipramine, trazadone, venlafaxine and mirtazepine are “likely to be beneficial” treatments for Generalized anxiety disorder on the basis of randomized placebo-controlled trials. The three controlled trials of antidepressant medication included in the Gould et al. (1997b) meta-analysis yielded a mean anxiety effect size of 0.57, and a high dropout rate of 33.5%, arguably due to the greater side-effects for these medications. Hoehn-Saric et al. (1988) found alprazolam and imipramine to be equally effective in reducing anxiety symptoms over 6 weeks in patients with DSM-III Generalized anxiety disorder without comorbid major depression or panic disorder. Rickels et al. (1993a) compared imiprimine, trazodone and diazepam over 8 weeks of treatment in a similar sample of patients. During the final 2 weeks of treatment, only imipramine produced significantly greater improvement in anxiety symptoms than placebo. The results also showed that, compared with the antidepressant medication, diazepam produced greater change in the first weeks of the treatment, had a greater effect on somatic symptoms, and fewer side-effects. However, the antidepressant medications were more effective in reducing psychic symptoms of anxiety. An 8-week trial of the specific serotonin reuptake inhibitor paroxetine in patients with DSM-IV Generalized anxiety disorder showed paroxetine to have equivalent treatment outcome to imipramine and the benzodiazepine 2-chloro-demethyldiazepam. Most recently, venlafaxine was found to provide significantly greater symptomatic relief than placebo after 6 weeks and then 6 months of treatment. Across the trial, a 69% response rate was achieved for the treatment group, compared with a 42-46% response rate for the placebo condition. Other medications have been studied in patients with Generalized anxiety disorder, such as abecarnil, gepirone, and hydroxyzine. Where controlled trials have been conducted, treatment effects have tended to be significantly greater than placebo-treated groups and equivalent to the other active medications studied.

The treatment literature confirms that benzodiazepine treatment is effective in the short-term treatment of generalized anxiety. However the high risk of dependence and the common return of symptoms following discontinuation preclude the usefulness of these drugs in a chronic disorder. Buspirone, with equal effectiveness and an absence of dependence, may well provide a better treatment option, but tends not to be widely prescribed. This may be due to the lag in effect, so that neither patients nor their doctors may be prepared to tolerate the several weeks that may occur before a decrease in anxiety is experienced. In many of the earlier pharmacological studies reviewed, it is unknown how many patients would have fulfilled DSM-IV diagnostic criteria. Furthermore, there is a paucity of long-term data for any pharmacotherapy, despite epidemiological evidence that for most individuals Generalized anxiety disorder is a chronic disorder. Given the increased importance of the concept of worry in the disorder, particular attention should be paid to the measurement of the cognitive components of anxiety. It is of interest that most studies that compared anxiolytic and antidepressant medications concluded that while overall the outcomes were equivalent, the antidepressant medication produce greater improvements in measures of psychic symptoms of anxiety.

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