Double-blind, placebo-substitution study of nefazodone in the prevention of relapse during continuation treatment of outpatients with major depression.

The efficacy of nefazodone in prevention of relapse of depression was evaluated in a 36-week double-blind, placebo-substitution, continuation treatment trial. After 16 weeks of acute, single-blind treatment with nefazodone, 131 patients responding to treatment and in stable remission were randomized in a 36-week double-blind trial to either nefazodone (n = 65) or placebo (n = 66). Patients were defined as having relapsed if they had a total score > or = 18 on the 17-item Hamilton Depression Scale on two consecutive visits or if they discontinued treatment for lack of efficacy. Relapse rates were significantly lower for patients randomized to continued nefazodone treatment than for patients switched to placebo. Kaplan-Meier estimates of relapse rates 9 months (36 weeks) after the end of acute treatment were 1.8% for nefazodone versus 18.3% for placebo (P = 0.009) by the Hamilton Depression Scale and 17.3% versus 32.8% (P = 0.028) by discontinuation for lack of efficacy. The mean modal dose of nefazodone was 412 mg/day at study endpoint. These results demonstrate the clinical effectiveness of up to 1 year's treatment (16 weeks acute and 36 weeks continuation) with nefazodone in depressed patients. Long-term efficacy of nefazodone was accompanied by a good safety profile without any weight gain and with minimal symptoms of withdrawal upon abrupt discontinuation of treatment.

Therapeutic dose range of nefazodone in the treatment of major depression.

The therapeutic dose range of nefazodone for treatment of major depression was examined in a series of placebo-controlled efficacy studies carried out during phase 2 and 3 premarketing clinical evaluation. Nefazodone is a new antidepressant drug with pharmacologic effects on both serotonin and norepinephrine neurotransmitters. The usual starting dose of nefazodone for depressed patients, unless they are being switched from a serotonin selective reuptake inhibitor (SSRI), is 100 mg. b.i.d. A lower starting dose is recommended for elderly patients or patients being treated with an SSRI. Following assessment of the patient's clinical response after the first week of therapy, the daily dose should be adjusted upward for most patients. In the efficacy studies, the majority of patients were being maintained on a dose of 300 to 500 mg daily at the end of the acute treatment period. The side effects of nefazodone most often related to dosage were sedation, nausea, and visual symptoms. Imipramine-treated patients, on the other hand, had a high incidence of dry mouth, constipation, and asthenia. In these studies, nefazodone was found to be effective and well tolerated by patients, the majority of whom were being maintained at a 300- to 500-mg/day dose, following an initial starting dose of 100 mg b.i.d.

Gepirone treatment of atypical depression: preliminary evidence of serotonergic involvement.

This is a report of a controlled trial of gepirone, a 5-hydroxytryptamine (5-HT1A) partial agonist azapirone related to buspirone, in the treatment of atypical depression. The azapirones are of particular interest because their highly selective actions on the serotonergic system may possibly make them useful pharmacologic probes and potentially selective therapeutic agents. Sixty outpatients meeting Columbia criteria for definite or probable atypical depression were enrolled in a double-blind, randomized, placebo-controlled, 8-week clinical trial at a single site. The dosage schedule was fixed flexible, with 10-mg capsules given on a thrice-daily schedule, with doses of up to 120 mg daily. The response rate at 8 weeks for the intention-to-treat sample analyzed with the last observation carried forward was 62% (18 of 29 patients) for gepirone and 20% (6 of 30 patients) for placebo (chi 2 = 9.1; df = 1; p < 0.001). Robust and consistent drug-placebo differences are seen across virtually all rating scales post-treatment. The effect of gepirone was consistent across the levels of concomitant variables, including duration of episode and presence of dysthymia or panic. Gepirone is a novel antidepressant that holds promise for the treatment of atypical depression and that may be of heuristic value because of its relatively specific actions on the serotonergic system.

Long-term treatment of depression with nefazodone.

The utility of double-blind continuation data in assessing long-term efficacy was evaluated in an analysis of data from the development program of a new antidepressant, nefazodone. The benefit of nefazodone therapy was examined during continuation treatment of patients who improved during the 6-8 week acute phase of efficacy studies. Discontinuation for lack of efficacy was used as an indicator of relapse. Pooled long-term data from the extension phases of placebo-controlled, acute efficacy trials were analyzed by the Kaplan-Meier method to estimate survival curves for time to discontinuation. Both nefazodone (p < .01) and imipramine (p < .05) were more effective than placebo during long-term continuation therapy. The findings demonstrate the value of double-blind continuation data in the evaluation of long-term drug benefit and provide an early assessment of nefazodone's effectiveness in continuation treatment of major depression.

Safety of graded symptom-limited exercise testing in patients with congestive heart failure.

The safety and end points of graded symptom-limited bicycle exercise were assessed in 607 patients before they were randomized to vasodilator or placebo in the Veterans Administration Cooperative Study-Vasodilator Heart Failure Trial. Their mean age was 58 years and left ventricular ejection fraction averaged 30%. The peak exercise responses were as follows: oxygen consumption, 14.5 +/- 3.9 ml/kg/min; heart rate, 132 +/- 24 beats/min; systolic blood pressure, 154 +/- 29 mm Hg. No major complications occurred with the baseline tests. The initial baseline test was stopped in only 10 patients (1.6%) for arrhythmias and in one patient for hypotension. Ventricular tachycardia assessed by ambulatory electrocardiographic monitoring during the second exercise test (before exercise, during exercise, and 4 hr after the test) revealed a prevalence of 5.7% during exercise and 28.8% during the rest of the monitoring period. This study has demonstrated that stable male patients with congestive heart failure can safely exercise on a bicycle ergometer to their peak effort in a well-supervised setting. In addition, we have demonstrated that ambulatory electrocardiographic monitoring is a better method than exercise testing to evaluate presence and extent of ventricular arrhythmias in patients with congestive heart failure.

Veterans Administration Cooperative Study on Vasodilator Therapy of Heart Failure: influence of prerandomization variables on the reduction of mortality by treatment with hydralazine and isosorbide dinitrate.

The Veterans Administration Cooperative Study on Vasodilator Therapy of Heart Failure was designed to determine whether vasodilator drugs could alter the survival of patients with chronic congestive heart failure treated with digoxin and diuretics. Among the 642 patients entered into the study, 273 were randomly assigned to placebo, 186 were randomly assigned to the combination of hydralazine and isosorbide dinitrate, and 183 patients were randomly assigned to prazosin; all patients were followed for periods ranging from 6 months to 5.7 years. Treatment with hydralazine-nitrate produced a 28% reduction in mortality compared with that in patients receiving placebo (95% confidence interval, 3% to 46%), whereas prazosin exerted no apparent beneficial effect. Data were further examined to determine if any baseline variables had an impact on the response to treatment. Mortality in the placebo group was higher in those with coronary artery disease, with a history of antiarrhythmic drug use, and with values lower than the median for ejection fraction and exercise tolerance. A reduction in mortality with hydralazine-isosorbide dinitrate was observed in all of the above pairs of subgroups as well as in those above and below 60 years of age and those with and without a history of hypertension or excess alcohol ingestion. The benefit of hydralazine and isosorbide dinitrate was particularly prominent in younger patients with a lower ejection fraction and those with a history of hypertension and without an alcoholic history.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study.

To evaluate the effects of vasodilator therapy on mortality among patients with chronic congestive heart failure, we randomly assigned 642 men with impaired cardiac function and reduced exercise tolerance who were taking digoxin and a diuretic to receive additional double-blind treatment with placebo, prazosin (20 mg per day), or the combination of hydralazine (300 mg per day) and isosorbide dinitrate (160 mg per day). Follow-up averaged 2.3 years (range, 6 months to 5.7 years). Mortality over the entire follow-up period was lower in the group that received hydralazine and isosorbide dinitrate than in the placebo group. This difference was of borderline statistical significance. For mortality by two years, a major end point specified in the protocol, the risk reduction among patients treated with both hydralazine and isosorbide dinitrate was 34 percent (P less than 0.028). The cumulative mortality rates at two years were 25.6 percent in the hydralazine--isosorbide dinitrate group and 34.3 percent in the placebo group; at three years, the mortality rate was 36.2 percent versus 46.9 percent. The mortality-risk reduction in the group treated with hydralazine and isosorbide dinitrate was 36 percent by three years. The mortality in the prazosin group was similar to that in the placebo group. Left ventricular ejection fraction (measured sequentially) rose significantly at eight weeks and at one year in the group treated with hydralazine and isosorbide dinitrate but not in the placebo or prazosin groups. Our data suggest that the addition of hydralazine and isosorbide dinitrate to the therapeutic regimen of digoxin and diuretics in patients with chronic congestive heart failure can have a favorable effect on left ventricular function and mortality.

Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study.

We conducted a multicenter, double-blind, placebo-controlled randomized trial of aspirin treatment (324 mg in buffered solution daily) for 12 weeks in 1266 men with unstable angina (625 taking aspirin and 641 placebo). The principal end points were death and acute myocardial infarction diagnosed by the presence of creatine kinase MB or pathologic Q-wave changes on electrocardiograms. The incidence of death or acute myocardial infarction was 51 per cent lower in the aspirin group than in the placebo group: 31 patients (5.0 per cent) as compared with 65 (10.1 per cent); P = 0.0005. Nonfatal acute myocardial infarction was 51 per cent lower in the aspirin group: 21 patients (3.4 per cent) as compared with 44 (6.9 per cent); P = 0.005. The reduction in mortality in the aspirin group was also 51 per cent--10 patients (1.6 per cent) as compared with 21 (3.3 per cent)--although it was not statistically significant; P = 0.054. There was no difference in gastrointestinal symptoms or evidence of blood loss between the treatment and control groups. Our data show that aspirin has a protective effect against acute myocardial infarction in men with unstable angina, and they suggest a similar effect on mortality.