### Studies in Outpatients with Depression

During its premarketing development, the efficacy of nefazodone was evaluated at doses within the therapeutic range in five well-controlled, short-term (6 to 8 weeks) clinical investigations. These trials enrolled outpatients meeting DSM-III or DSM-IIIR criteria for major depression. Among these trials, two demonstrated the effectiveness of nefazodone, and two provided additional support for that conclusion.

One trial was a 6 week dose-titration study comparing nefazodone in two dose ranges (up to 300 mg/day and up to 600 mg/day [mean modal dose for this group was about 400 mg/day], on a BID schedule) and placebo. The second trial was an 8 week dose-titration study comparing nefazodone (up to 600 mg/day; mean modal dose was 375 mg/day), imipramine (up to 300 mg/day), and placebo, all on a BID schedule. Both studies demonstrated nefazodone, at doses titrated between 300 mg to 600 mg/day (therapeutic dose range), to be superior to placebo on at least three of the following four measures: 17 Item Hamilton Depression Rating Scale or HDRS (total score), Hamilton Depressed Mood item, Clinical Global Impressions (CGI) Severity score, and CGI Improvement score. Significant differences were also found for certain factors of the HDRS (e.g., anxiety factor, sleep disturbance factor, and retardation factor). In the two supportive studies, nefazodone was titrated up to 500 or 600 mg/day (mean modal doses of 462 mg/day and 363 mg/day). In the fifth study, the differentiation in response rates between nefazodone and placebo was not statistically significant. Three additional trials were conducted using subtherapeutic doses of nefazodone.

Overall, approximately two thirds of patients in these trials were women, and an analysis of the effects of gender on outcome did not suggest any differential responsiveness on the basis of sex. There were too few elderly patients in these trials to reveal possible age-related differences in response.

Since its initial marketing as an antidepressant drug product, additional clinical investigations of nefazodone have been conducted. These studies explored nefazodone’s use under conditions not evaluated fully at the time initial marketing approval was granted.

### Studies in “Inpatients”

Two studies were conducted to evaluate nefazodone’s effectiveness in hospitalized depressed patients. These were 6 week, dose-titration trials comparing nefazodone (up to 600 mg/day) and placebo, on a BID schedule. In one study, nefazodone was superior to placebo. In this study, the mean modal dose of nefazodone was 503 mg/day, and 85% of these inpatients were melancholic; at baseline, patients were distributed at the higher end of the 7 point CGI Severity scale, as follows: 4 = moderately ill (17%); 5 = markedly ill (48%); 6 = severely ill (32%). In the other study, the differentiation in response rates between nefazodone and placebo was not statistically significant. This result may be explained by the “high” rate of spontaneous improvement among the patients randomized to placebo.

### Studies of “Relapse Prevention in Patients Recently Recovered (Clinically) from Depression”

Two studies were conducted to assess nefazodone’s capacity to maintain a clinical remission in acutely depressed patients who were judged to have responded adequately (HDRS total score ≤ 10) after a 16 week period of open treatment with nefazodone (titration up to 600 mg/day). In one study, nefazodone was superior to placebo. In this study, patients (n = 131) were randomized to continuation on nefazodone or placebo for an additional 36 weeks (1 year total). This study demonstrated a significantly lower relapse rate (HDRS total score ≥ 18) for patients taking nefazodone compared to those on placebo. The second study was of appropriate design and power, but the sample of patients admitted for evaluation did not suffer relapses at a high enough incidence to provide a meaningful test of nefazodone’s efficacy for this use.

### Comparisons of Clinical Trial Results

Highly variable results have been seen in the clinical development of all antidepressant drugs. Furthermore, in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisons among the findings of studies evaluating the effectiveness of different antidepressant drug products are inherently unreliable. Because conditions of testing (e.g., patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc.) vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference due to one or more of the confounding factors just enumerated.