Fluoxetine: a randomized clinical trial in the maintenance of weight loss.

Because current weight-reduction treatments have considerable recidivism, a therapy that could help patients maintain weight loss would be of benefit. A six-center, randomized, double-blind trial compared the effects of the specific serotonin uptake inhibitor, fluoxetine hydrochloride, and placebo on maintenance of weight loss. Obese outpatients who had lost > or = 3.6 kg after 8 weeks of single-blind fluoxetine 60 mg/day in the qualification phase (N=317 [70.4% of patients entered]; mean +/- standard deviation [SD] weight loss, 6.8 +/- 2.8 kg) were randomly assigned to fluoxetine 20 mg/day (N=104), fluoxetine 60 mg/day (N=106), or placebo (N=107) for 40 weeks (maintenance phase). Patients received minimal nutrition/dietary counseling. Qualification phase clinic visits were biweekly; maintenance phase visits were monthly for 4 months, then bimonthly for 6 months. Patients treated with fluoxetine 60 mg/day continued to lose weight for 8 additional weeks (16 weeks total; maximum mean +/- SD weight loss, 7.2 +/- 4.6 kg); those treated with fluoxetine 20 mg/day or placebo began to regain weight. Mean weights remained below baseline values at week 48 (all groups); treatment differences were not statistically significant. Study completion rates were comparable (fluoxetine 20 mg/day, 67.3%; fluoxetine 60 mg/day, 56.6%; placebo, 67.3%; p = 0.175). Among commonly reported adverse events (> 10% incidence), only asthenia was reported statistically significantly (p < 0.050) more frequently with fluoxetine than with placebo. Few patients discontinued for any single adverse event. Fluoxetine 60 mg/day was effective for a longer period than fluoxetine 20 mg/day or placebo in maintaining weight loss. Overall, fluoxetine was safe and well tolerated.

Fluoxetine: no association with suicidality in obsessive-compulsive disorder.

Since (a) obsessive-compulsive disorder (OCD) may involve serotonergic neural transmission abnormalities also though to be related to regulation of suicide and aggression, (b) comorbidity between OCD and depression is substantial, and (c) depression is a major risk factor for suicide, a comprehensive analysis of clinical trial data was undertaken to assess the potential association of fluoxetine, a serotonin uptake inhibitor, and suicidality (suicidal acts and ideation). Pooled data from clinical trials comparing fluoxetine (n = 266) and placebo (n = 89) in patients with DSM-IIIR OCD were analyzed retrospectively. No suicidal acts occurred during placebo lead-in or double-blind therapy. Mean Hamilton Depression Scale item 3 (suicide item) scores improved statistically significantly with fluoxetine compared with placebo. Worsening in suicidal ideation was statistically significantly more frequent with placebo than with fluoxetine. Emergence of substantial suicidal ideation (change in baseline item 3 score of 0 or 1 to 3 or 4) was numerically greater with placebo than with fluoxetine (3.6% vs. 1.7%; not statistically significant). The incidence of suicidality in fluoxetine-treated patients with OCD was low, compared favorably with rates in corresponding placebo-treated patients, and was well within the range of estimates in previous studies of patients with OCD. These controlled clinical trial results suggest no undue risk of suicidality in patients with OCD treated with fluoxetine.

Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression.

OBJECTIVE: A comprehensive meta-analysis of clinical trial data was performed to assess the possible association of fluoxetine and suicidality (suicidal acts and ideation). DESIGN: Retrospective analysis of pooled data from 17 double blind clinical trials in patients with major depressive disorder comparing fluoxetine (n = 1765) with a tricyclic antidepressant (n = 731) or placebo (n = 569), or both. MAIN OUTCOME MEASURES: Multiple data sources were searched to identify patients with suicidal acts. Suicidal ideation was assessed with item 3 of the Hamilton depression rating scale, which systematically rates suicidality. Emergence of substantial suicidal ideation was defined as a change in the rating of this item from 0 or 1 at baseline to 3 or 4 during double blind treatment; worsening was defined as any increase from baseline; improvement was defined as a decrease from baseline at the last visit during the treatment. RESULTS: Suicidal acts did not differ significantly in comparisons of fluoxetine with placebo (0.2% v 0.2%, p = 0.494, Mantel-Haenszel adjusted incidence difference) and with tricyclic antidepressants (0.7% v 0.4%, p = 0.419). The pooled incidence of suicidal acts was 0.3% for fluoxetine, 0.2% for placebo, and 0.4% for tricyclic antidepressants, and fluoxetine did not differ significantly from either placebo (p = 0.533, Pearson's chi 2) or tricyclic antidepressants (p = 0.789). Suicidal ideation emerged marginally significantly less often with fluoxetine than with placebo (0.9% v 2.6%, p = 0.094) and numerically less often than with tricyclic antidepressants (1.7% v 3.6%, p = 0.102). The pooled incidence of emergence of substantial suicidal ideation was 1.2% for fluoxetine, 2.6% for placebo, and 3.6% for tricyclic antidepressants. The incidence was significantly lower with fluoxetine than with placebo (p = 0.042) and tricyclic antidepressants (p = 0.001). Any degree of worsening of suicidal ideation was similar with fluoxetine and placebo (15.4% v 17.9%, p = 0.196) and with fluoxetine and tricyclic antidepressants (15.6% v 16.3%, p = 0.793). The pooled incidence of worsening of suicidal ideation was 15.3% for fluoxetine, 17.9% for placebo, and 16.3% for tricyclic antidepressants. The incidence did not differ significantly with fluoxetine and placebo (p = 0.141) or tricyclic antidepressants (p = 0.542). Suicidal ideation improved significantly more with fluoxetine than with placebo (72.0% v 54.8%, p less than 0.001) and was similar to the improvement with tricyclic antidepressants (72.5% v 69.8%, p = 0.294). The pooled incidence of improvement of suicidal ideation was 72.2% for fluoxetine, 54.8% for placebo, and 69.8% for tricyclic antidepressants. The incidence with fluoxetine was significantly greater than with placebo (p less than 0.001) and did not differ from that with tricyclic antidepressants (p = 0.296). CONCLUSIONS: Data from these trials do not show that fluoxetine is associated with an increased risk of suicidal acts or emergence of substantial suicidal thoughts among depressed patients.

Fluoxetine versus trazodone: efficacy and activating-sedating effects.

BACKGROUND: The efficacy and safety of fluoxetine (N = 65; median sustained dose, 20 mg/day) and of trazodone (N = 61; median sustained dose, 250 mg/day) were compared in a trial in outpatients with major depressive episode. The incidence and temporal patterns of activation and sedation were also assessed. METHOD: Men and women who met DSM-III criteria for nonpsychotic major depressive episode (but with a current episode greater than or equal to 4 weeks) and had a 21-item Hamilton Rating Scale for Depression (HAM-D21) score greater than 20 were selected. After single-blind placebo was administered for 1 week, eligible patients were randomized to double-blind fluoxetine or trazodone treatment for up to 6 weeks. Efficacy (HAM-D21, Clinical Global Impressions Scales for Severity and Improvement, Patient Global Impressions Scale for Improvement, Guild Memory Test) and adverse events were evaluated weekly. RESULTS: The HAM-D21 score improved within both treatment groups (p less than .001). The groups were similar with respect to endpoint mean HAM-D21 improvement. For individual adverse events that developed or worsened during therapy, more fluoxetine-treated patients reported rhinitis and tremor (p less than or equal to .05), while more trazodone-treated patients reported somnolence and dizziness (p less than or equal to .05). More combined events suggesting activation (agitation, anxiety, nervousness, insomnia) were reported with fluoxetine than with trazodone (15.4% vs. 3.3%, p less than or equal to .05), while more combined events suggesting sedation (somnolence, asthenia) were reported with trazodone than with fluoxetine (42.6% vs. 21.5%, p less than or equal to .05). Discontinuation rates for activation and sedation did not differ between treatments. Numerically, more sedation (21.5%) than activation (15.4%) was reported with fluoxetine. CONCLUSIONS: There was little clinical difference between treatments with regard to efficacy and safety. The occurrence and temporal patterns of activation and sedation differed within and between treatments.

Pattern analysis shows beneficial effect of fluoxetine treatment in mild depression.

In a multicentered study, 372 patients with mild major depressive disorder with a Hamilton Rating Scale for Depression (HAM-D) score of 15 to 19 were randomly assigned to 6 weeks of treatment with placebo or 20 mg, 40 mg, or 60 mg/day of fluoxetine. Patients were rated weekly for improvement and the appearance of side effects. Pattern analysis of treatment response showed more patients in the active drug treatment groups having a persistent or a delayed persistent response, the types of response specifically associated with active treatment. Analyses of mean changes in treatment measures showed little difference among treatment groups. This may be explained in part by different distributions in outcome, placebo patients having had a higher frequency of mild improvement with fewer negative and very positive outcomes. Response rate analyses favor the active treatments numerically, but only one of the comparisons is statistically significant. These findings suggest a specific role for fluoxetine treatment in mildly depressed patients who do not respond promptly or who respond inconsistently to nonspecific treatment.

Dose-effect and concentration-effect relationships of pinacidil and hydrochlorothiazide in hypertension.

To determine dose-effect and concentration-effect relationships in hypertension for pinacidil and hydrochlorothiazide when given alone and together, we conducted a randomized, double-blind, 4 X 3 factorial, modified fixed-dose multicenter trial. Three hundred and eighty-four patients with essential hypertension (supine diastolic blood pressure, 95 to 110 mm Hg) were assigned to one of 12 groups that received all combinations of four doses of pinacidil (0, 12.5, 25, and 37.5 mg, b.i.d.) with three doses of hydrochlorothiazide (0, 12.5, and 25 mg, b.i.d.). Significant dose- and concentration-effect relationships were seen for pinacidil and hydrochlorothiazide on diastolic blood pressure. For pinacidil, dose- and concentration-effect relationships were steeper after the dose than before the dose. A significant interaction with hydrochlorothiazide was noted such that, when combined with 12.5 mg hydrochlorothiazide, 12.5 mg pinacidil had near-maximal effects on blood pressure at both peak and trough. Edema occurred in 47% of those who received 37.5 mg pinacidil monotherapy (19% discontinued). The administration of 12.5 mg pinacidil with 12.5 mg hydrochlorothiazide appears to be optimal for efficacy and safety.

Monitoring versus interim analysis of clinical trials: a perspective from the pharmaceutical industry.

The definitions of "interim analysis" and "monitoring" of clinical trials are often ambiguous in the current literature. The resulting confusion can lead to erroneous conclusions and misguided decisions, especially when activities that are operational or observational are evaluated in a probabilistic sense as inferential. The authors seek to define "interim analysis" and "monitoring" in a mutually exclusive fashion. These definitions will then provide the opportunity to review and categorize existing clinical trial practices and procedures. This will clarify such issues as "when to look" and "when to pay a price" (e.g., test size and power) and characterize such issues in the context of pharmaceutical industry drug development.

Placebo response in depression: a search for predictors.

Although 30-40% of depressed patients respond to placebo treatment, few predictors of placebo response have been identified. We evaluated patients with moderate to severe depression who had received placebo for 3-6 weeks in multicenter clinical trials (Study 1, n = 125; Study 2, n = 88). Placebo response rates (greater than 50% improvement in Hamilton total depression score) were 38.4% and 30.7%, respectively. Despite differences in treatment outcome, baseline clinical and demographic characteristics were similar for responders and nonresponders. The studies confirmed the substantial placebo response in moderately to severely depressed patients and suggested chronicity may be a predictor.