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The development of a new antidepressant medication is usually accompanied by a concern as to whether or not the compound will be sufficiently effective in clinically important subgroups of patients (e.g., depressed patients with increased severity of symptomatology, patients with melancholic features, and patients whose illness is recurrent). This paper describes results of a pooled analysis of four placebo-controlled studies included in the development program of the antidepressant nefazodone. These studies involved a total of 247 patients receiving nefazodone in a dose of up to 600 mg/day, 251 patients on placebo, and 166 patients receiving imipramine. For purposes of the analysis, patients were defined as being more severely depressed (Clinical Global Impressions scale [CGI] psychopathology score of at least markedly ill), having melancholia using DSM-III-R criteria, or having recurrent major depression (using DSM-III-R criteria). Efficacy was assessed by improvement in the Hamilton Rating Scale for Depression (17 items; HAM-D-17) Total score and CGI scale. Nefazodone (mean dose at endpoint = 379 mg/day) was effective in the management of depressed patients with moderate or severe symptomatology, depressed patients with or without melancholic features, and patients with single or recurrent episodes of depression.

Comprehensive review of safety data from approximately 3500 patients who received nefazodone in premarketing clinical trials demonstrates the drug to be very well tolerated, with a favorable side effect profile compared with other antidepressant drugs. Nefazodone treatment was associated with fewer side effects than were the control drugs. The incidence of side effects was generally low, and treatment discontinuations for adverse effects were less frequent with nefazodone than with imipramine and comparable with fluoxetine. No late-appearing side effects or toxicity emerged during the long-term treatment (1 year or longer) of several hundred patients. There were no drug-related fatalities and no evidence that nefazodone caused specific organ toxicity, although some cardiovascular side effects were noted (e.g., asymptomatic reduced systolic blood pressure, asymptomatic sinus bradycardia). Experience in 488 elderly patients treated with nefazodone yielded no evidence of increased susceptibility of older patients to nefazodone-associated adverse experiences, including those pertaining to the cardiovascular system. However, treatment should be initiated at a reduced dose in elderly patients because of reduced hepatic clearance of nefazodone in this age group. Final dose range may be similar in healthy younger and older patients. Although nefazodone may interact with some other medications (e.g., increases at steady state in AUC: alprazolam, twofold; triazolam, fourfold), drug-drug interactions involving patients have been clinically minor. On the basis of the inhibition of cytochrome P450 3A4 isoenzyme by nefazodone in vitro, coadministration of terfenadine or astemizole with nefazodone is contraindicated because nefazodone can increase the plasma levels of these two drugs. Extensive clinical experience provides substantial evidence that nefazodone is an extremely safe and effective treatment for depression, with important advantages over existing therapies. Therapeutic benefits include a low incidence of clinically troublesome side effects and lack of unwanted psychic activation, sexual dysfunction, weight change, and the cardiotoxicity of other antidepressants.

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.

Background: Nefazodone hydrochloride, a 5-HT2 receptor antagonist that selectively inhibits serotonin reuptake, was evaluated in a double-blind, dose-finding study of novel design, involving 240 patients with major depression., Method: Patients were randomly assigned to three treatment groups and received either placebo (2-6 capsules per day), a lower-dose range of nefazodone (50-300 mg/day), or a higher-dose range of nefazodone (100-600 mg/day) for 6 weeks., Results: At the end of treatment, the Hamilton Rating Scale for Depression and the clinician- and patient-rated Inventory for Depressive Symptomatology scores showed significant improvement (p < or = .05) for patients receiving higher-dose range nefazodone (mean = 392 mg/day) compared with placebo treatment. The percentage of responders (at least "much improved" on the Clinical Global Impressions-Improvement scale) in the higher-dose range nefazodone group (58%) was significantly greater (p < or = .05) than in the placebo group (39%). The treatment group receiving nefazodone in the lower-dose range was not differentiated in clinical response from placebo controls. The rate of discontinuation for adverse experience (14%) was similar for patients treated with higher-dose range nefazodone and placebo., Conclusion: The findings of this study indicate that nefazodone is an effective and well-tolerated antidepressant drug, with a recommended therapeutic dose range of 100 to 600 mg/day and a starting dose of 100 mg b.i.d.

A meta-analysis of six randomized, placebo-controlled, double-blind trials was carried out to evaluate the effectiveness of the new antidepressant nefazodone in relieving symptoms of anxiety and agitation associated with major depression. Nefazodone blocks serotonin2 (5-HT2) receptors and selectively inhibits serotonin (5-HT) reuptake. This pharmacologic profile may confer clinical benefits that differ from those of other antidepressants, such as tricyclics (TCAs) and serotonin selective reuptake inhibitors (SSRIs). The data base included 817 patients with major depression and baseline 17-item Hamilton Rating Scale for Depression (HAM-D-17) scores > or = 18; 345 received placebo, 288 imipramine, and 184 nefazodone. Both nefazodone and imipramine exhibited antidepressant efficacy compared with that of placebo, irrespective of baseline anxiety levels. Statistically significant improvement in Hamilton Rating Scale for Anxiety (HAM-A), HAM-D anxiety factor, HAM-D psychic anxiety item, and HAM-D agitation item scores was observed with both active treatments. Nefazodone-treated patients showed significantly greater improvement in somatic anxiety (HAM-D item 11) ratings than placebo-treated patients from Week 4 through end of treatment (p < or = .01), while imipramine-treated patients did not differ from placebo patients on this item. Nefazodone-treated patients improved more rapidly (as early as Week 1) than imipramine- and placebo-treated patients on agitation (HAM-D item 9) (p < or = .01). Nefazodone was found to have an excellent safety profile and was well tolerated, with 5% of nefazodone patients prematurely discontinuing treatment for adverse experiences compared with 17% for imipramine and 5% for placebo treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Nefazodone hydrochloride, a 5-HT2 receptor antagonist and serotonin (5-HT) uptake inhibitor, was evaluated in four Phase 3 double-blind, imipramine- and placebo-controlled studies involving outpatients with major depression., Method: Patients who qualified for well-controlled efficacy trials in major depression were enrolled in a series of active- and placebo-controlled trials to establish the comparative efficacy of nefazodone and a standard tricyclic antidepressant drug. The primary efficacy measures employed were the 17-item Hamilton Rating Scale for Depression (HAM-D-17) and the Clinical Global Improvement (CGI) scale. Safety profiles were also compared as well as survival analyses of double-blind acute and continuation treatment of patients in efficacy trials., Results: Three of four Phase 3 active- and placebo-controlled studies showed nefazodone to be an effective antidepressant drug with overall efficacy generally similar to that of imipramine. The remaining study did not differentiate either active drug from placebo controls. Superiority of nefazodone and imipramine over placebo was evidenced by greater improvement on core depression symptoms in addition to the primary outcome measures (HAM-D-17 and CGI). The incidence of side effects and premature treatment discontinuations for imipramine-treated patients was higher than for nefazodone therapy. Both drugs showed evidence of continuing efficacy during long-term treatment with significantly fewer dropouts (p < .05) than for placebo controls., Conclusion: Nefazodone, an antidepressant that modulates serotonin receptors and enhances serotonin-mediated neurotransmission, has been shown to be an effective and well-tolerated new antidepressant drug with greater patient acceptability and safety than imipramine.