STUDY2
In a 6-week study, alprazolam was compared to imipramine and placebo in 723 patients with moderate to severe depression and associated anxiety symptoms (6). Alprazolam effectively reduced the symptoms of anxiety and depression, was comparable to imipramine, and, at the doses used, showed a faster onset of activity. For patients who completed the study, the mean final daily dose of alprazolam was 2.9 mg compared with 131.8 mg of imipramine. This study employed both the Hamilton Psychiatric Rating Scale for Depression (HAM-D) (7) and the HARS. An overall view of the results on both of these scales is provided (Figs. 1 and 2). Both active drugs were clearly more effective than placebo on all measurements. The HAM-D rated alprazolam as effective as imipramine at each of four evaluation points. In addition, on the HAM-D total score, patients receiving alprazolam had a lower mean score at week 1 than did those taking imipramine (p < 0.001) (Fig. 1). This difference is reflected in the mean scores of several of the symptoms clusters from the same scale (Table 1). Similarly, patients treated with alprazolam showed a significantly greater re -
sponse on the HARS than imipramine-treated patients at weeks 1, 2, and 4. On the HARS total score, imipramine did not achieve efficacy equivalent to alprazolam until the assessment at week 6 (Fig. 2). At the end of the 6-week period, patients treated with alprazolam demonstrated a greater reduction in the HARS Somatic Cluster score than did patients who had received imipramine (Table 2). Also, after 6 weeks alprazolam therapy demonstrated efficacy equal to imipramine in reducing the HARS Psychic Cluster score (Table 3). Alprazolam was more effective than imipramine (p < 0.017) on the somatic symptom cluster of the HARS at each assessment and on the psychic symptom cluster at week 1 (Table 4). 
Patients taking alprazolam exhibited improvement of 40% or greater from their initial scores in four HARS item scores: depressed mood, insomnia, and cardiovascular and respiratory components. The imipramine group showed a 40% or greater improvement in initial HARS item scores: depressed mood, insomnia, respiratory, and cognitive components (Figs. 3 to 7). The mean scores on all three Physician’s Global Impressions questions show both active drugs better than placebo at all four assessments and that patients receiving alprazolam responded better than those taking imipramine at weeks
1 and 2. When asked how much the patient had changed from the initial score and what the therapeutic effect of the drug was, the alprazolam group also had better scores than the imipramine group at week 6. Calculating the percent of patients who fell into each category on the three Physician’s Global Impressions questions disclosed a similar pattern. Both active drugs were more effective than placebo (p <= 0.001) at each assessment on all three questions. More patients taking alprazolam than imipramine showed good response at week 1 (p <= 0.001) (Figs. 8-10). In determining the change in the patients’ conditions from the initial assessment (rated as "much improved" or "very much improved"), using the Physician’s Global Impressions as criteria, 74% of the alprazolam group, 71% of the imipramine group, and 54% of the placebo group were responders at the end of the study (Fig. 10).
The Physician’s Global Impressions showed that the therapeutic effects of alprazolam and imipramine were significantly better than placebo. On the Patient’s Global Impressions scale, which determined how the patient felt since taking the drug, alprazolam was better than imipramine for the first week (p <= 0.017), but not at the subsequent assessments (Figs. 11 and 12). The Hopkins Symptom Checklist showed both active drugs to be more effective than placebo at each evaluation period on the total score and on the depression item (p <=. 0.01). Regarding the five other items on the checklist, each active drug
was more effective than placebo at approximately the same number of evaluations (p<= 0.017) (Table 5). Treatment-emergent symptoms (TES) were tabulated by the number of incidents (Table 6) and by the number of patients reporting TES (Table 7). In both tables, dry mouth, light-headedness, tachycardia and palpitations, blurred vision, and constipation appear most frequently in the imipramine group. Only drowsiness appears most frequently in the alprazolam group. Headache and nervousness were experienced most by more patients receiving placebo. Almost as many patients taking imipramine as placebo reported either the development or worsening of insomnia during the study; about half as many patients taking alprazolam complained of insomnia as a TES. 
Side effects caused 50 patients to drop out; these included 10 of 243 patients treated with placebo, 10 of 236 patients treated with alprazolam, and 30 of 244 patients treated with imipramine (Fig. 13). The most common adverse reaction to alprazolam was drowsiness. Fewer patients receiving alprazolam than imipramine or pla
cebo dropped out of the study because of ineffective medication. A significantly greater number of patients in the placebo group (80) discontinued treatment for this reason than did patients treated with alprazolam (10) or imipramine (19). Initial vital signs and physical examination and laboratory assay data were comparable for the three treatment groups. No clinically significant changes were observed during the study