Effects of concurrent diazepam treatment on the outcome of exposure therapy in agoraphobia. Absence of neuropsychologic deficits in patients receiving long-term treatment with alprazolam-XR for panic disorder. Alprazolam and exposure alone and combined in panic disorder with agoraphobia. A controlled study in London and Toronto.
In a study designed to evaluate the impact of benzodiazepine use on the outcome of behaviour therapy, 91, severe, chronic agoraphobics (46 BDZ users and 45 non-users) were randomly allocated on a double-blind basis to in vivo exposure with low-dose diazepam (ED) or placebo (EP). Drug doses were adjusted on the basis of weekly psychiatric assessments over weeks 1-4. Patients had 8 x 2 hr exposure sessions (weeks 5-12) and were then withdrawn from medication (weeks 13-16). Re-assessments were completed at weeks 4, 12 and 16, and follow-up assessments at approx 20, 46 and 72 weeks. In the analysis of the results, the clinical outcome was evaluated in relation to the therapeutic regime (ED vs EP) and prior BDZ use (users vs non-users). The results showed that the ED group had greater changes in anxiety than the EP group during the drug manipulation phases (anxiety increasing during BDZ withdrawal). There were no group differences in agoraphobic symptoms and no evidence that the outcome of the behavior therapy was significantly affected by concurrent BDZ treatment. There were significant improvements in agoraphobic symptoms over the treatment period, with no evidence for relapse of treatment gains on withdrawal from BDZ, nor for differential responses over the one year follow-up. Initial differences between users and non-users were less marked than expected, although there was a trend for more drop-outs among users across both ED and EP groups. Studies to date on the effects of benzodiazepines on neuropsychologic function have yielded conflicting data with respect to the type, severity, and duration of deficits that may be induced by these agents. As part of a placebo-controlled trial of alprazolam-XR (extended release) administered in combination with cognitive-behavioral therapy in patients with panic disorder, a battery of tests was used to measure neuropsychologic function. Thirty-eight outpatients were randomly assigned to receive either alprazolam-XR or placebo. Dosages were titrated up so that the alprazolam group (N = 18) received a mean dose of 4 mg/day (reduced in two patients because of sedative side effects). Neuropsychologic function after 6 weeks of therapy at the target dosage was compared with baseline assessments in each group. Both groups showed a statistically significant improvement from baseline to repeated assessments on measures of attention, executive functioning, psychomotor speed, and visual memory (p < 0.001); these gains were attributed to a practice effect. No significant changes were noted in measures of learning, verbal memory, or reaction time, and neither group showed any deterioration from baseline to retesting in any aspect of neuropsychologic function. These findings call into question the assumption that long-term benzodiazepine therapy produces significant neuropsychologic deficit in patients with diagnosed anxiety disorders. A cross-national randomised trial of alprazolam for chronic panic disorder with agoraphobia was run. Compared with previous trials it had three new features: an exposure therapy contrast group, a six-month treatment-free follow-up, and a low rate of early placebo drop-outs ('non-evaluables'). The dose of alprazolam was high (5 mg/day). The 154 patients had eight weeks of: alprazolam and exposure (combined treatment); or alprazolam and relaxation (a psychological placebo); or placebo and exposure; or placebo and relaxation (double placebo). Drug taper was from weeks 8 to 16. Follow-up was to week 43. Results were similar at both sites. Treatment integrity was good. All four treatment groups, including double placebo, improved well on panic throughout. On non-panic measures, by the end of treatment, both alprazolam and exposure were effective, but exposure had twice the effect size of alprazolam. During taper and follow-up, gains after alprazolam were lost, while gains after exposure were maintained. Combining alprazolam with exposure marginally enhanced gains during treatment, but impaired improvement thereafter. The new features put previous trails in a fresh light. By the end of treatment, though gains on alprazolam were largely as in previous studies, on phobias and disability they were half those with exposure. Relapse was usual after alprazolam was stopped, whereas gains persisted to six-month follow-up after exposure ceased. Panic improved as much with placebo as with alprazolam or exposure.
The review established the paucity of high quality evidence investigating the efficacy of psychotherapy combined with benzodiazepines for panic disorder. Currently, there is inadequate evidence to assess the clinical effects of psychotherapy combined with benzodiazepines for patients who are diagnosed with panic disorder.