Fluvoxamine, a selective serotonin reuptake inhibitor, was investigated in a 6-week double-blind study among severely ill inpatients with DSM-III major depression. All but 1 patient also fulfilled ...criteria for melancholia. Following a 3-day placebo wash-out patients were randomly assigned to fluvoxamine, imipramine or placebo. Sixty of 81 patients completed at least 2 weeks following wash-out and were evaluated for efficacy. Analysis of covariance (controlling for baseline scores) showed significant (p less than 0.05) differences on CGI severity and BPRS total and a similar trend (p = 0.08) on the Hamilton Depression Scale. Fluvoxamine was superior (p less than or equal to 0.02) to both placebo and imipramine on these measures. Fluvoxamine's most common adverse effects were nausea and agitation. The number of fluvoxamine patients withdrawn for side-effects was less than imipramine and not significantly different than placebo. Fluvoxamine was not associated with significant changes in vital signs, ECG or laboratory tests. The results therefore indicate that fluvoxamine is a safe and highly effective treatment for hospitalized patients with major depression.
Fluoxetine is the first selective serotonin reuptake inhibitor antidepressant to be marketed in the U.S. In this double-blind trial fluoxetine was compared with imipramine and placebo among 198 ...outpatients with DSM-III major depression, of whom 145 completed at least 2 weeks of active treatment and were evaluated for efficacy. Significantly fewer patients in each active drug group terminated early due to lack of efficacy compared to placebo. Both imipramine and fluoxetine were significantly superior to placebo on most measures. There were no consistently significant differences between the two active drugs although a trend favored imipramine on a number of measures. Fluoxetine was generally well tolerated. Significantly more imipramine than placebo patients terminated early due to side-effects while the fluoxetine-placebo difference was not significant. The results support previous studies which suggest fluoxetine's superior side-effect profile and the approximate antidepressant equivalence of fluoxetine and TCAs.
The chronic and recurrent nature of major depression is well recognized, and recent data suggest that maintenance therapy with full-dose pharmacotherapy (i.e., the dose used to treat the index ...episode) is effective in preventing relapse and recurrence. We present results from a 1-year, double-blind trial of paroxetine and imipramine in patients who successfully completed a 6-week acute course of therapy. A total of 717 outpatients were included in the 6-week, randomized, double-blind, placebo-controlled comparative study of paroxetine and imipramine conducted at six centers. At the end of the acute treatment phase, patients showing a therapeutic response were eligible to enter a long-term extension of the study in which they would continue to receive the same drug (or placebo) in double-blind fashion for up to 1 year. Of the 219 patients who entered the long-term phase, 94 received paroxetine, 79 received imipramine, and 46 received placebo. During the 1-year maintenance study, both paroxetine and imipramine were more effective than placebo in maintaining euthymia among patients who had responded to short-term treatment. However, approximately twice as many imipramine-treated patients dropped out of the study prematurely because of adverse experiences compared to paroxetine-treated patients, suggesting that paroxetine is more readily tolerated than imipramine during long-term treatment.
Thirty outpatients between the ages of 60 and 85 with DSM-III Major Depression entered an 8 week randomized, double-blind comparison of desipramine and adinazolam mesylate, a triazolobenzodiazepine ...derivative. Outcome was assessed on several measures including the Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Rating Scale, Clinical Global Impressions (CGI), the 35-item Self-Rating Symptom Scale, and Carroll Depression Scale. Patients in both groups demonstrated a highly significant decrease in average HDRS scores (p less than 0.001) over the course of the study. Adinazolam was associated with significantly greater reduction in average HDRS scores by the third day. Repeated measures analysis of variance showed a significantly greater reduction in HDRS scores for adinazolam over the course of the study. The study medications were associated with distinct patterns of adverse reactions. Desipramine more often produced dry mouth, constipation and nervousness, while adinazolam was more likely to cause drowsiness and lightheadedness. Three of these elderly patients, all of whom were taking desipramine reported at least one fall during the study. Adinazolam may be a promising agent in the treatment of depression in the elderly.
The antidepressant efficacy and safety of venlafaxine was shown previously in 6-week, placebo-controlled trials. We evaluated the long-term safety and clinical acceptability of venlafaxine and ...imipramine in a double-blind, parallel-group, comparative study. Two hundred ninety depressed outpatients were treated with venlafaxine, and an additional 91 received imipramine for as long as clinically necessary, up to 1 year. The total daily dose of each drug could vary from 75 to 225 mg. The Clinical Global Impressions Scale and a therapeutic response rate that was based on Clinical Global Impressions Scale-Improvement and incorporated discontinuation information were used to evaluate efficacy. Safety determinations and patient subjective ratings were used to evaluate safety and clinical acceptability. During the study, the adverse events were generally mild to moderate and most subsided with continued treatment; the most frequent were nausea for venlafaxine and dry mouth for imipramine. The anticholinergic side effect burden was significantly higher in the imipramine group than in the venlafaxine group. Venlafaxine was judged significantly more acceptable than imipramine, on the basis of the subjective ratings by patients. Fewer venlafaxine-treated patients than imipramine-treated patients withdrew because of adverse events and unsatisfactory response. There was a consistent trend in the therapeutic response rates in favor of venlafaxine that reached statistical significance at months 2, 6, and 12. In this long-term study, patient acceptability was greater for venlafaxine than for imipramine, suggesting therapeutic advantages for venlafaxine in the long-term treatment of depression. Additional studies with other active comparators are underway to confirm and extend these encouraging results.
There are few published placebo-controlled clinical trials demonstrating the efficacy of the newer antidepressants in markedly or severely depressed hospitalized patients. This study demonstrates the ...efficacy of nefazodone compared with placebo in the treatment of patients hospitalized for major depression.
Nefazodone and placebo treatment were compared in a 6-week trial of 120 patients hospitalized for DSM-III-R diagnosed major depression (without psychosis) at 2 study centers. Efficacy was evaluated using standard psychiatric rating scales, and patients were monitored for safety.
Nefazodone treatment resulted in a significant reduction (p < .01) of the 17-item Hamilton Rating Scale for Depression (HAM-D-17) total score compared with placebo from the end of the first treatment week through the end of the study (-12.2 nefazodone vs. -7.7 placebo). At the end of the trial, significantly more nefazodone-treated patients (50%) than placebo-treated patients (29%) had responded, as indicated by their Clinical Global Impressions-Improvement score (p = .021) or by a > or = 50% reduction in their HAM-D-17 scores (p = .017). Significantly more patients treated with nefazodone (36%) than placebo-treated patients (14%) had a HAM-D-17 score < or = 10 at the end of treatment (p = .004). Significant treatment differences (p < .01) in favor of nefazodone were also seen in the Montgomery-Asberg Depression Rating Scale; the HAM-D retardation, anxiety, and sleep disturbance factors; and HAM-D item 1 (depressed mood). Patients with dysthymia in addition to major depression also showed significant improvement (p < .05) when treated with nefazodone, with significant differences in response rates seen as early as week 2 and through the end of the trial. The mean nefazodone dose was 491 mg/day at the end of week 2 and 503 mg/day at the end of treatment. Nefazodone was well tolerated, and the number of patients discontinuing owing to adverse events was small, with no significant safety issues noted in either treatment group. Fewer nefazodone-treated than placebo-treated patients discontinued owing to lack of efficacy.
Nefazodone was superior to placebo in the treatment of marked to severe major depression in patients requiring hospitalization. The clinical benefit of nefazodone was evident as early as the first week of treatment as judged by several measures of efficacy, with significant differences from placebo sustained throughout the trial.
The azapirone class of anxiolytic drugs is being evaluated for clinical use in the treatment of depression. Buspirone, a serotonin (5-hydroxytryptamine, 5-HT) partial agonist active at the 5-HT1A ...receptor subtype, was evaluated in the treatment of depression in a series of five placebo-controlled, parallel group studies involving 382 patients with DSM-III major depression and significant associated anxiety symptoms (both Hamilton depression HAM-D and Hamilton anxiety HAM-A scales greater than or equal to 18). Buspirone therapy was initiated at 15 mg/day with individual dose titration to a maximum of 90 mg/day and resulted in marked improvement in both depressive and anxiety symptoms. Analyses of the composite data base from the five studies show significant (p less than 0.05) improvement in mean HAM-D, HAM-A, and Clinical Global Impression-Global Improvement scale ratings for buspirone-treated compared with placebo-treated patients. Of particular interest was significant improvement in cardinal depression symptoms, e.g., depressed mood, guilt, work and interest, anergia, and diurnal variation of mood. Subset analyses revealed that patients with melancholic-type major depression and patients with more severe symptoms (judged by higher initial HAM-D or HAM-A total scores) responded better to buspirone than did patients who were less ill. The buspirone dose most frequently associated with clinically significant improvement was 40 mg/day. Gepirone, an analogue of buspirone with highly selective binding affinity for the 5-HT1A receptor subtype, also shows promise of antidepressant efficacy in preliminary controlled clinical trials. These data suggest that azapirones, which as partial agonists modulate 5-HT1A receptor function, have clinically important antidepressant properties.
The selective serotonin-1A receptor partial agonist anxiolytics represent a new class of pharmacologic agents that have demonstrated efficacy in the treatment of generalized anxiety disorder (GAD). ...These compounds offer a completely different pharmacologic approach to this disorder from previous medications. The selective 5-hydroxytryptamine-1A (5-HT1A) anxiolytics buspirone, gepirone, ipsapirone, and SM-3997 have several important new and unique features that will be reviewed in this paper. These features include no cross-tolerance with alcohol or benzodiazepines, no evidence of abuse or misuse potential, and no withdrawal symptoms or rebound anxiety on cessation of therapy. The 5-HT1A anxiolytics have no muscle relaxant, sedative, or anticonvulsant properties and do not impair psychomotor functioning. They do have a slower onset of effect than standard benzodiazepines-clinical response is usually noted in 1-3 weeks. The side effect profile is quite different from that of the benzodiazepines. It includes gastrointestinal symptoms such as nausea and diarrhea, headache, dizziness, and restlessness. Some patients with GAD who have received chronic (greater than 1 month) benzodiazepine therapy may not respond as well to these compounds initially as will patients with no prior benzodiazepine treatment, especially if the benzodiazepine has been discontinued only recently. These compounds, buspirone in particular, have been shown to have excellent maintenance and prophylactic properties and to be well tolerated with long-term therapy (greater than 3 months). Because of their unique mechanism of action and side effect profile, and no evidence of misuse or abuse potential or interference with mental acuity, these compounds represent a definite advance in the pharmacologic management of GAD.
