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The aim of this study was to make a preliminary investigation of the efficacy and safety of zatosetron maleate, a selective 5-hydroxytryptamine-3 receptor antagonist for patients with a broad range of anxiety symptoms. A double-blind, parallel, placebo-controlled pilot study was conducted in 43 patients, aged 18 to 65 years, scoring >17 on the Hamilton Rating Scale for Anxiety (HAM-A). Patients were randomly assigned to either a fixed oral dose of 0.2, 1, or 5 mg of zatosetron or placebo for 4 weeks, followed by a 2-week placebo phase. Enhanced blinding procedures reduced the influence of side effects on efficacy ratings and obscured phases of the research design to patient and clinician. A change in HAM-A scores from baseline to endpoint was the principal efficacy measure; HAM-A Psychic and Somatic subscales, the Symptom Checklist-90, Montgomery-Asberg Depression Rating Scale, and Clinical Global Impressions Scale subscales provided secondary change indices. Adverse events (AEs) (spontaneously mentioned and elicited with the Udvalg for Kliniske Undersøgelser side effect rating scale), vital signs, electrocardiographic findings, and laboratory analytes were compared among treatment groups. Eighty-eight percent of the patients met the criteria for generalized anxiety disorder. No statistically significant differences in outcome measures differentiated among the four treatment groups. However, a pattern of greater change in the HAM-A scores seemed to favor zatosetron over placebo. Placebo was associated with only modest HAM-A score changes and a 30% response rate. The greatest numeric decrease in the HAM-A score and the highest response rate (45%) occurred in the groups receiving 0.2 and 1 mg of zatosetron. The secondary measures of efficacy demonstrated similar outcomes. There were no deaths or serious AEs reported in this study. This pilot study demonstrated that zatosetron at doses of 0.2 to 5 mg/day was safe. Although statistical significance was not achieved, the results show a greater numeric trend toward reducing anxiety with zatosetron than with placebo.

Concomitant use of psychoactive medications is a common practice in most clinical trials of antidepressant medications. However, the relative therapeutic impact of such use on trial results has not been the subject of much attention. We conducted a meta-analysis to determine whether concomitant use of psychoactive medications confounded the efficacy or safety results of a series of fluoxetine trials. Data were evaluated from 25 randomized, double-blind clinical trials comparing fluoxetine with placebo or a tricyclic antidepressant (TCA) in 4,016 patients with major depression. We compared incidence rates of concomitant use of anxiolytics, sedatives, and antipsychotics between treatments. In addition, we compared the change in total score for the 21-Item Hamilton Depression Rating Scale (HAMD21): incidence rates of any worsening, emergence, or improvement in psychomotor agitation; and incidence of suicidal acts and any worsening, emergence, or improvement in suicidal ideation between treatment groups among patients taking/not taking a sedative. Anxiolytic and antipsychotic drug use was uncommon (8.3% and 0.9% overall use, respectively) and did not substantially increase over time. Sedative drugs were used most often (29.6% overall), but only 29.8% of the fluoxetine-treated patients took one or more doses. Regarding efficacy, fluoxetine was superior to placebo in decreasing HAMD21 total scores among patients taking/not taking sedatives. Effects on safety were assessed by examining agitation and suicidal ideation. Use of sedatives did not affect the change in the HAMD agitation score; scores were similar in patients receiving fluoxetine, placebo, and TCAs. In all treatment groups, anxiolytic use tended to increase as the HAMD anxiety score increased. Fluoxetine was superior to placebo in treating suicidal ideation, and the concomitant use of sedatives did not influence this effect. Overall, concomitant use of psychotropic medications in the fluoxetine depression clinical trials was uncommon. Our meta-analysis demonstrated that the clinical efficacy and safety of fluoxetine were not confounded by the concomitant use of medications.

Psychomotor agitation, a common clinical feature of major depression, may first emerge or intensify during pharmacotherapy. Whether agitation is part of the underlying course of depression or iatrogenic complicates treatment planning. We analyzed data from blinded clinical trials involving 4,737 patients with major depression assigned to a selective serotonin reuptake inhibitor (fluoxetine), a comparator antidepressant (usually a tricyclic antidepressant [TCA]), or placebo. Item 9 of the Hamilton Depression Rating Scale was used to assess the degree of psychomotor agitation. The vast majority of depressed patients exhibited baseline psychomotor agitation. The rate of increased agitation from baseline during acute pharmacotherapy was comparable between fluoxetine and either placebo or TCAs. Substantial emergence of psychomotor agitation also occurred at a similar incidence across the three treatment groups and typically appeared within the first 3 wk. Improvement in agitation was significantly more prominent (P < 0.001) among fluoxetine-treated than among placebo-treated patients. Fluoxetine-treated patients demonstrated numerically superior improvement rates compared with TCA-treated patients; however, this difference was not significant. Data derived from this large series of clinical trials suggested no evidence that either fluoxetine or TCAs induced psychomotor agitation at rates exceeding the natural course of the disorder over time (placebo cohort). On the contrary, pharmacotherapy with either fluoxetine or TCAs was typically associated with diminished agitation, probably as part of the response pattern of depression.

Parkinson's disease, because of its progressive degenerative nature, is associated with increased disability and mortality compared with mortality in the general population. We examined mortality data from three clinical trials involving 1,330 patients with Parkinson's disease treated with pergolide as an adjunct to levodopa or levodopa/carbidopa therapy. The ratio of observed deaths to expected deaths in the general population of the same age, gender, race distribution, and period of observation was 2.3 for the 3 studies combined. The ratio is lower than that in Parkinson's disease patients treated prior to the introduction of levodopa, consistent with ratios with levodopa and levodopa combination therapy. The ratio is slightly higher than in Parkinson's disease patients treated with levodopa and levodopa combination therapy, which may be attributable to differing patient characteristics in the populations studied.

Obesity is a major health care concern because of its associated medical complications and increased mortality. Despite a myriad of short-term weight loss strategies and the motivation of improving health, patients have difficulty maintaining reduced weight. Pharmacologic agents, such as fluoxetine, a selective serotonin uptake inhibitor, have been investigated as adjunctive therapy to standard weight management programs. Extended therapy with fluoxetine has demonstrated clinically meaningful benefits on weight loss and obesity-associated medical conditions in double-blind placebo-controlled studies. However, the magnitude of these benefits for individuals vary. Such findings are consistent with the belief that the obesity syndrome has differing etiologies. Accordingly not all patients are likely to benefit from a particular therapy. Studies should identify patient subgroups that are more likely to respond to a specific therapy. In this study of 719 fluoxetine-treated and 722 placebo treated patients in four multicenter, randomized, double-blind, long-term clinical trials, we investigated possible predictors of a beneficial long-term outcome from fluoxetine therapy. Patients' age, current smoking activity, and baseline uric acid concentration were predictors of a meaningful long-term treatment effect. Further review of the weight loss patterns of patients achieving long-term success provided the basis for a treatment monitor. Use of the predictors and the treatment monitor are strategies to maximize the benefits of therapy through improved patient selection and monitoring during a therapeutic program.

A common presentation for major depression includes psychomotor agitation. However, this subtype has been the infrequent subject of controlled investigation during depression trials. Yet, the subcategorization of agitated depression has historically been associated with the belief that older, sedating compounds have a superior risk:benefit profile. In the 8-week, double-blind, randomized, parallel trial, 124 subjects with Research Diagnostic Criteria-compatible agitated depression were randomized to either imipramine (IMI) or fluoxetine (FLU). Both compounds proved to be similarly effective as measured by change in HAM-D17, HAM-D17 response, and HAM-D17 remission rates. Similar comparability was seen in secondary measures of agitation, anxiety, suicidality, and global impressions. However, of note, a statistically significant difference in early discontinuations because of intolerable adverse events emerged. Whereas 43.5% of IMI subjects discontinued early, only 9.7% of FLU subjects (p < 0.001) did. Significantly more central nervous system events characterized the IMI than the FLU subgroup (IMI, 24.2%, vs. FLU, 6.5%; p = 0.006). In conclusion, among subjects with major depression, subtype agitated, the risk:benefit profile favored FLU over IMI. This was driven by the superior tolerance of FLU. No evidence emerged in support of the clinical hypothesis that a "sedating" agent is the treatment of choice for this group. The results are important when striving to maximize compliance with pharmacotherapy in order to minimize recidivism and associated psychological and economic morbidity.

We modified criteria for judging successful obesity treatment proposed by Atkinson to provide objective criteria for successful benefit from weight reduction programs with respect to data from a clinical trial. The criteria include assessments of changes in both weight-related factors (e.g. excess weight, excess body fat) and obesity-related risk factors (e.g. hypertension, hyperglycemia, hyperlipemia). To demonstrate the use of this methodology, we applied the criteria in an analysis of eight randomized, double-blind controlled trials comparing fluoxetine (n = 522) with placebo (n = 504) for weight loss. The results suggest these criteria can be useful for evaluating a treatment program or for comparing treatments from clinical trials.

Background: The presence or absence of anxiety has traditionally determined choice of an antidepressant ("activating" or "sedating"); however, there is little scientific support for the construct. We conducted a meta-analysis to determine whether comorbid anxiety affected efficacy or predisposed patients to specific adverse events., Method: Data were evaluated from 19 randomized, double-blind clinical trials comparing fluoxetine with placebo or a tricyclic antidepressant (TCA) or both in 3,183 patients with major depression (Cochran-Mantel-Haenszel, Mantel-Haenszel incidence difference, analysis of variance, and Pearson's chi-square methods). On the basis of the anxiety/somatization factor within the 21-item Hamilton Rating Scale for Depression (HAM-D21), patients were characterized as anxious (score > or = 7) or nonanxious (score < 7)., Results: Fluoxetine was significantly (p < or = .05) more effective than placebo in treating both anxious and nonanxious major depression (mean improvement in HAM-D21 total score, 11.0 versus 8.1 and 8.1 versus 5.5, respectively). Fluoxetine was also statistically significantly more effective than placebo in reducing the HAM-D21 anxiety/somatization factor score (anxious, all patients). The efficacy of fluoxetine and TCAs was comparable (all measures, all groups). Discontinuations for adverse events were statistically significantly higher with fluoxetine than placebo (anxious, 15.2% versus 3.8%; nonanxious, 13.2% versus 6.7%) and with TCAs than fluoxetine (anxious, 28.9% versus 15.5%; nonanxious, 34.1% versus 19.0%). Among events suggestive of "activation" or "sedation," incidence rates ranged from 0.0% to 32.9%; discontinuation rates were low (0.0% to 4.1%), except for somnolence with TCAs (9.4% to 13.2%)., Conclusion: Anxiety in major depression does not appear to affect response to an antidepressant. Therefore, antidepressant selection should be determined by an agent's overall risk:benefit ratio, not the presence or absence of anxiety.

A re-analysis of the profile of adverse events observed in controlled clinical trials in summarized. The data confirm that the side-effects of fluoxetine therapy are different from those of the tricyclic antidepressants (TCAs), both in type and frequency. Moreover, the superior tolerability of fluoxetine compared with the TCAs is confirmed by the significantly lower rate of premature discontinuation in the fluoxetine-treated patients than in the TCA-treated patients.

Double-blind, controlled clinical trial data were evaluated to assess a hypothetical relationship between fluoxetine and suicidality (suicidal acts and ideation) in patients with mood (n = 5,655) and nonmood disorders (n = 4,959) (Mantel-Haenszel incidence difference method). In mood disorders, act rates (suicide attempts/completions) were low (treatment differences nonsignificant). Substantial suicidal ideation emerged less frequently with fluoxetine than placebo and was comparable with fluoxetine and tricyclic antidepressants. Improvement in ideation was greater with fluoxetine than placebo; it was comparable with fluoxetine and tricyclic antidepressants (United States trials) and greater with tricyclic antidepressants than fluoxetine (international trials). In nonmood disorders, no suicides occurred. Act and emergent ideation rates were low (treatment differences nonsignificant). Results do not suggest a causal relationship between pharmacotherapy and emergence of suicidality. Fluoxetine or tricyclic antidepressants reduce suicidal ideation and may protect against the emergence of substantial suicidal ideation.

Fluoxetine, a serotonin uptake inhibitor, and amitriptyline, a tricyclic antidepressant, were compared in a 5-week, multicenter, double-blind, randomized trial in 136 out-patient men and women, aged 21-70 years, with major depressive disorder. Overall efficacy was comparable with fluoxetine and amitriptyline [Hamilton 21-Item Rating Scale for Depression (HAM-D21), Raskin, Covi, Clinical Global Impressions-Severity and -Improvement, Patient's Global Impressions]. Mean +/- standard deviation decreases in HAM-D21 total score were 12.9 +/- 9.9 and 11.6 +/- 10.3 (p = 0.423), respectively. Response rates (> or = 50% decrease in HAM-D21 total score) for patients treated > or = 4 weeks were 46.7% and 66.0% (p = 0.039) and remission rates (HAM-D21 total score < or = 7) were 18.3% and 28.3% (p = 0.209), respectively. Response and remission rates for all patients were comparable with fluoxetine and amitriptyline. Study completions were higher with fluoxetine than amitriptyline (87.7% vs 66.2%; p = 0.003). Discontinuations for adverse events were higher with amitriptyline than fluoxetine (22.5% vs 6.2%; p = 0.007). More treatment-emergent nausea and insomnia were reported with fluoxetine (p < or = 0.05); more anticholinergic and orthostatic events and weight gain were reported with amitriptyline (p < or = 0.05). Statistically, but not clinically, significant changes were observed in vital signs. Both fluoxetine and amitriptyline were effective treatments for out-patients with major depressive disorder. Fluoxetine had a more favorable safety profile than amitriptyline.

Serotonin uptake inhibitors are generally considered activating antidepressants. To assess rates and temporal patterns of activation and sedation as well as dose-effect relationships, adverse event data were evaluated from a fixed-dose study comparing placebo and fluoxetine 5, 20, and 40 mg/day in the treatment of major depressive disorder (N = 363) and two fixed-dose studies pooled together comparing placebo and fluoxetine 20, 40, and 60 mg/day in the treatment of major depressive disorder (N = 746). The adverse events nervousness, anxiety, agitation, and insomnia were considered indicative of activation; somnolence and asthenia were considered indicative of sedation. Activation and sedation were both statistically significant (p less than or equal to 0.05) treatment-emergent phenomena, but dose-effect relationships differed. Activation rates were relatively stable between 5 and 40 mg/day, and then increased at 60 mg/day. Sedation rates increased linearly to 40 mg/day and then were comparable at 40 and 60 mg/day. Discontinuations for either phenomenon were uncommon. The temporal patterns of first occurrences and persistence of activation and sedation differed. First occurrences of activation peaked early and declined over time with all doses. First occurrences of sedation also peaked early with all doses, but there may have been greater variability in first occurrences of sedation over time with lower doses. Persistent occurrences of sedation may decline less over time than persistent occurrences of activation.

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.

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.

The effects of high-dose fluoxetine (median 80 mg/day), standard-dose imipramine (median 200 mg/day), and placebo were studied in 706 outpatients meeting DSM-III criteria for major depressive disorder. Baseline psychomotor activity of each patient was prospectively categorized as agitated, retarded, or neither. Rates of occurrence of total and significant (leading to discontinuation) activating adverse events (insomnia, agitation, anxiety, nervousness) and sedating events (somnolence, asthenia) were compared between treatments on an overall basis and within categories of baseline psychomotor activity. Additionally, these rates were compared across baseline psychomotor activity for each treatment. Efficacy was evaluated on an overall basis and with respect to baseline psychomotor activity. There was more total activation with fluoxetine than placebo (p = 0.008), but total activation with fluoxetine (28%) showed only a trend (p = 0.092) for being greater than with imipramine (21%). Discontinuations for activation with fluoxetine (5%) did not differ from imipramine (5%). Sedation and discontinuations for sedation with both fluoxetine and imipramine significantly exceeded placebo. The only drug-drug difference in discontinuations was for sedation where imipramine (11%) exceeded fluoxetine (5%; p = 0.008). Only for the occurrence of sedation with imipramine (47% among patients retarded at baseline) was there a significant association with baseline psychomotor activity (p = 0.021). Both fluoxetine and imipramine were superior to placebo and equal in efficacy in decreasing total Hamilton Rating Scale for Depression (HAM-D), the sleep disturbance HAM-D factor, and the anxiety/somatization HAM-D factor scores. These improvements were independent of baseline psychomotor activity.

Data regarding open-label treatment with fluoxetine following failure to respond to tricyclic antidepressants (TCAs) or intolerance of TCA side effects, suggest a response rate between 51.4% and 62.1%, depending on the definition of TCA refractoriness employed. Double-blind study of this issue would extend these findings. Fluoxetine is well tolerated in patients unable to tolerate TCAs. Within this population, more than 80% of patients unable to tolerate TCAs found fluoxetine acceptable. Fluoxetine, as an alternative to polypharmaceutical augmentation, may represent a logical choice as the next step in therapy for a patient who has initially been treated with a TCA and has proven refractory or intolerant.