Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders.

Olanzapine and risperidone, both second-generation antipsychotic agents, represent two different pharmacologic strategies. Although they share some in vitro properties, they differ by virtue of their chemical structure, spectrum of receptor binding affinities, animal neuropharmacology, pharmacokinetics, and in vivo neuroimaging profile. Based on such differences, it was hypothesized that the two compounds would show distinct safety and/or efficacy characteristics. To test this hypothesis, an international, multicenter, double-blind, parallel-group, 28-week prospective study was conducted with 339 patients who met DSM-IV criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. Results of the study indicated that both olanzapine and risperidone were safe and effective in the management of psychotic symptoms. However, olanzapine demonstrated significantly greater efficacy in negative symptoms (Scale for Assessment of Negative Symptoms summary score), as well as overall response rate (> or = 40% decrease in the Positive and Negative Syndrome Scale total score). Furthermore, a statistically significantly greater proportion of the olanzapine-treated than risperidone-treated patients maintained their response at 28 weeks based on Kaplan-Meier survival curves. The incidence of extrapyramidal side effects, hyperprolactinemia, and sexual dysfunction was statistically significantly lower in olanzapine-treated than risperidone-treated patients. In addition, statistically significantly fewer adverse events were reported by olanzapine-treated patients than by their risperidone-treated counterparts. Thus, the differential preclinical profiles of these two drugs were also evident in a controlled, clinical investigation. Olanzapine seemed to have a risk-versus-benefit advantage.

Blind, controlled, long-term study of the comparative incidence of treatment-emergent tardive dyskinesia with olanzapine or haloperidol.

OBJECTIVE: Tardive dyskinesia is a serious and common complication of neuroleptic treatment. Olanzapine is a novel antipsychotic agent exhibiting regional mesolimbic dopaminergic selectivity and a broad-based pharmacology encompassing serotonin, dopamine, muscarinic, and adrenergic receptor binding affinities. The authors' goal was to compare the incidence of tardive dyskinesia among patients receiving olanzapine and those receiving the conventional dopamine 2 antagonist haloperidol. METHOD: Data were analyzed from three actively controlled and blind long-term responder studies of subjects meeting DSM-III-R criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder treated with olanzapine (N = 707, up to 20 mg/day, 237 median days of exposure) or haloperidol (N = 197, up to 20 mg/day, 203 median days of exposure) who did not have evidence of tardive dyskinesia at baseline. All of the subjects had a chronic disease course (mean greater than 10 years), and there were no significant between-treatment group differences in demographic or disease characteristics. The Abnormal Involuntary Movement Scale and research diagnostic criteria for tardive dyskinesia were used to define the comparative incidence rates of long-term treatment-emergent tardive dyskinesia. RESULTS: The incidence of newly emergent tardive dyskinesia at any visit after baseline, at the final visit, and at the final two clinical assessments was statistically significantly lower among olanzapine-treated patients than among haloperidol-treated patients. CONCLUSIONS: These findings support an atypical extrapyramidal symptom profile and the potential of a significantly lower risk of tardive dyskinesia with olanzapine than with haloperidol among patients requiring maintenance antipsychotic treatment.

Extrapyramidal symptoms and tolerability of olanzapine versus haloperidol in the acute treatment of schizophrenia.

BACKGROUND: A relative lack of extrapyramidal symptoms (EPS, i.e., the syndromes of dystonia, parkinsonism, akathisia, dyskinesia) is one criterion used to determine whether an antipsychotic is "atypical." The extrapyramidal symptom profiles of the novel antipsychotic olanzapine and the conventional antipsychotic haloperidol were compared in a population of 2606 patients from three well-controlled prospective clinical trials. METHOD: Extrapyramidal symptom data were analyzed for 1796 patients treated with olanzapine (5 to 20 mg/day) and 810 patients treated with haloperidol (5 to 20 mg/day) for up to 6 weeks of therapy. Patients were monitored weekly by three methods of extrapyramidal symptom assessment: (1) detection of extrapyramidal adverse events (signs and symptoms) by casual observation, nonprobing inquiry, and spontaneous report; (2) objective rating scale scores: and (3) use of concomitant anticholinergic medications. Emergence of EPS was assessed by (1) analysis of the incidence of extrapyramidal syndrome categories based on adverse events, (2) the incidence of extrapyramidal syndromes based on categorical analysis of rating scale scores, (3) analysis of mean maximum change in rating scale scores, and (4) categorical analysis of anticholinergic medication use. Outcome of EPS was assessed by (1) analysis of mean change in rating scale scores at endpoint and (2) mean anticholinergic use at endpoint. RESULTS: Olanzapine was statistically significantly (p = .014, p < .001) superior to haloperidol in all four analyses related to emergence of EPS and in the two analyses related to outcome. Furthermore, during acute treatment, statistically significantly fewer patients treated with olanzapine (0.3%) discontinued the study because of any extrapyramidal adverse event than patients treated with haloperidol (2.7%, p < .001). CONCLUSION: Olanzapine exhibited a statistically significantly lower extrapyramidal symptom profile than the conventional antipsychotic haloperidol at comparably effective antipsychotic doses. The lower extrapyramidal symptom profile with olanzapine was evident despite statistically significantly more frequent use of anticholinergic drugs among haloperidol-treated patients. Fewer olanzapine-treated than haloperidol-treated patients discontinued because of EPS, suggesting that olanzapine should contribute to better compliance with longer term maintenance treatment, with minimal anticholinergic-associated events.

Analysis of mortality in pergolide-treated patients with Parkinson's disease.

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.

Long-term fluoxetine treatment of bulimia nervosa. Fluoxetine Bulimia Nervosa Research Group.

BACKGROUND: A large collaborative 8-week study has shown fluoxetine to be effective and safe in treating patients with bulimia nervosa. The present study evaluated fluoxetine over 16 weeks. METHOD: Fifteen US out-patient psychiatry clinics conducted a double-blind parallel study in men and women with DSM-III-R bulimia nervosa (483 patients entered, 398 randomised [3:1 ratio, fluoxetine 60 mg/day or placebo], 225 completed). Outcome measures included change in vomiting and binge-eating episodes per week. Eating Disorder Inventory, Clinical Global Impressions and Patient's Global Impression. RESULTS: Compared with placebo, fluoxetine treatment resulted in significantly greater reductions in vomiting (F[1,360] = 14.73, P < 0.0001) and binge-eating (F[1,360] = 14.39, P = 0.0002) episodes per week at endpoint and improvement in other outcome measures. Adverse event, vital sign and laboratory analyses indicated that fluoxetine was safe. CONCLUSION: Fluoxetine appeared to be safe and effective in patients with bulimia nervosa for up to 16 weeks.

A double-blind, placebo-controlled clinical trial of fluoxetine in geriatric patients with major depression. The Fluoxetine Collaborative Study Group.

Depression in the geriatric population is a frequent, serious, and potentially reversible disorder, yet relatively few blinded, controlled, antidepressant trials have been reported. A number of age related issues complicate safe and effective pharmacotherapy. In a 6-week, double-blind trial in moderately to severely depressed (nonpsychotic) outpatients over age 60, fluoxetine (N = 335) was statistically significantly more efficacious than placebo (N = 336) in overall response (43.9% vs. 31.6%, p = .002) and remission (31.6% vs. 18.6%, p < .001) rates. Analyses of early discontinuations because of an adverse drug event revealed no statistically significantly greater rate with fluoxetine (n = 39; 11.6) than was seen with placebo (n = 29; 8.6%). These results corroborate that major depression in an older population is responsive to antidepressant pharmacotherapy. Specifically, fluoxetine, at a conventional 20-mg dose, was both safe and effective relative to placebo in this special population.

Long-term weight loss: the effect of pharmacologic agents.

We reviewed 20 English-language weight-reduction studies, reported between 1967 and March 1993, of the effect of > or = 6 mo of pharmacologic therapy on weight loss and its maintenance to determine the clinical benefits of extended treatment, propose treatment guidelines, and identify future research needs. Pharmacologic agents included phentermine, mazindol, fenfluramine, dexfenfluramine, and fluoxetine. Study designs varied with respect to blinding, use of a single agent vs a combination, dosing, length of therapy, patient selection, adjunctive therapy, and visit frequency. At endpoint, weight loss varied from study to study but a plateauing of weight loss or weight regain was observed after approximately 6 mo. The benefits of extended treatment appear to outweigh the risks for those patients who are unable to lose sufficient weight without pharmacologic therapy but who maintain adequate weight loss with long-term pharmacologic therapy. Future studies should define and evaluate pharmacologically responsive and unresponsive subgroups.

A multicenter investigation of fixed-dose fluoxetine in the treatment of obsessive-compulsive disorder.

OBJECTIVES: To determine the effectiveness of fluoxetine hydrochloride at fixed doses of 20 mg/d, 40 mg/d, and 60 mg/d in patients with obsessive-compulsive disorder (OCD) and to evaluate its safety. METHODS: Fixed-dose fluoxetine hydrochloride (20 mg/d, 40 mg/d, 60 mg/d) was compared with placebo in two randomized, double-blind, parallel, 13-week trials of identical design in 355 outpatients with OCD aged 15 to 70 years (DSM-III-R criteria; 1 year's duration or longer; depression secondary if present). RESULTS: Fluoxetine (all doses) was significantly (P < or = .001) superior to placebo on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score (mean baseline-to-end-point decrease, 4.6, 5.5, and 6.5 vs 0.9, respectively, studies pooled) and other efficacy measures (P < or = .01). A trend suggesting greater efficacy at 60 mg/d was observed. Most patients (79.2%) completed the study. Eight adverse events were statistically significantly more frequent with fluoxetine and one, with placebo. For some events, incidence tended to increase with increasing dosage; however, few patients discontinued treatment for any single event. CONCLUSION: Fluoxetine was associated with a statistically significant reduction in OCD severity, including time engaged in obsessional and/or compulsive behaviors. Adverse events infrequently led to study discontinuation.

Absence of a relationship between adverse events and suicidality during pharmacotherapy for depression.

This study tested the hypothesis that some patients treated with an antidepressant who develop adverse events (e.g., activation, akathisia) experience emergent suicidality specifically associated with such events. Seventeen double-blind, controlled clinical trials conducted in the United States and Canada with 3,065 patients with major depression were evaluated for treatment-emergent adverse events (events that first occurred or worsened during therapy) and suicidality (a suicidal act or emergence of substantial suicidal ideation or both) with fluoxetine, placebo, and tricyclic antidepressants. Nine relevant adverse event clusters were evaluated: activation, sedation, activation and sedation, decreased libido, mania, psychosis, psychosis and mania, acute brain syndrome, and violence. Incidence rates were determined for suicidality that was and was not temporally associated with an adverse event cluster and were analyzed within and across treatments (incidence difference method). Most patients experienced neither a cluster event nor suicidality. Where suicidality was reported, it generally was not in temporal association with an adverse event cluster. In no cluster was the incidence of suicidality statistically significantly higher when reported in temporal association with an event than when not. Suicidality was associated infrequently with treatment-emergent activation and at comparable rates across treatments. No increased risk of suicidality associated with an adverse event cluster was observed between the treatment groups (fluoxetine versus tricyclic anti-depressants; fluoxetine versus placebo). These results from double-blind, placebo- and comparator-controlled fluoxetine clinical trials in patients with major depression do not suggest a relationship between a treatment-emergent adverse event pattern and suicidality in this population.

Fluoxetine: a randomized clinical trial in the treatment of obesity.

Fluoxetine hydrochloride (Lovan, Eli Lilly and Company, Indianapolis, Indiana, USA), a specific serotonin uptake inhibitor, was compared with placebo in 458 obese outpatients in a 52-week double-blind randomized ten-site trial to study its effect on weight reduction. Patients in the fluoxetine and placebo groups were predominantly Caucasian (81% and 85%, respectively) and female (81% and 79%, respectively), with a mean body mass index (BMI) of 36.2 and 35.8 kg/m2, respectively, and a mean age of 43 years (both groups). Fluoxetine therapy (60 mg/day) resulted in statistically significantly (P < or = 0.05) greater mean weight loss than placebo to week 28. Although some patients continued to lose weight throughout the 52-week therapy period, maximum mean weight loss occurred at week 20. There was no treatment difference at 52 weeks. The change in visit frequency (biweekly to week 8, monthly to week 20, then bimonthly to week 52) may have affected results. Patients with higher baseline BMIs (> 40 kg/m2) attained and maintained a greater weight loss than patients with lower baseline BMIs (< 40 kg/m2). Two sites demonstrated greater efficacy than the study as a whole. The use of nutrition counselling at one site and behaviour modification at the other, or other site-to-site differences, may account for the improved efficacy. Fluoxetine was well tolerated and appeared to be safe therapy for the treatment of obesity with efficacy demonstrated for 28 weeks.

Fluoxetine, placebo, and tricyclic antidepressants in major depression with and without anxious features.

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.

Evaluation of suicidality during pharmacologic treatment of mood and nonmood disorders.

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 compared with imipramine in the treatment of inpatient depression. A multicenter trial.

Fluoxetine and imipramine were compared in a six-week, double-blind, randomized trial in 118 men and women, ages 18 to 70 years, hospitalized for major depressive disorder. Treatment groups were comparable at baseline. Median maintenance doses were: fluoxetine, 80 mg/day; imipramine, 200 mg/day. Efficacy with fluoxetine and imipramine was comparable: none of the between-treatment differences was statistically significant. Mean +/- standard deviation baseline HAMD21 total scores and change (last-visit-carried-forward analysis), respectively, were fluoxetine, 28.0 +/- 5.3 and -8.5 +/- 9.9; imipramine, 27.0 +/- 5.8 and -11.9 +/- 9.0. Response and remission rates, respectively, were fluoxetine, 54.5 and 21.2%; imipramine, 60.0 and 34.3%. Discontinuations for adverse events were comparable (fluoxetine, 21.4%; imipramine, 22.6%). Common treatment-emergent events with fluoxetine were dry mouth (28.6%), constipation (17.9%), and somnolence (17.9%); those with imipramine were dry mouth (58.1%), constipation (32.3%), and headache (22.6%). Fluoxetine was as effective as imipramine in this population of inpatients.

Analyses of suicidality in double-blind, placebo-controlled trials of pharmacotherapy for weight reduction.

BACKGROUND: The obese who seek therapy may also have depression and thus a risk for suicidality (suicidal acts and ideation). For this reason and because of interest in the potential impact of a medication with antidepressant properties on suicidality in a population without a primary diagnosis of depression, we performed a comprehensive analysis of suicidality data from clinical trials in patients seeking weight-reduction therapy. METHOD: Suicidality data from 11 double-blind controlled trials in the United States Investigational New Drug fluoxetine obesity clinical trial data base (3819 randomized outpatients) were reviewed. Trials lasted 6 to 60 weeks (continuous and intermittent therapy designs). They included obese men and women (median body mass index, 35.0 kg/m2). Trials excluded patients treated with antidepressants. Incidence of suicidality was analyzed by the incidence difference method. RESULTS: No fatal suicidal acts occurred. One suicide attempt was reported in a patient receiving placebo after prior fluoxetine therapy (intermittent therapy trial). The overall incidence of suicidal ideation among fluoxetine-treated and placebo-treated patients in the obesity clinical trials was 0.24%. The difference in incidence of emergent suicidal ideation in fluoxetine-treated (0.23%) and placebo-treated patients (0.27%) was not statistically significant. CONCLUSION: Based on these analyses of controlled clinical trials, suicidality occurs but has a low incidence rate in the obese who seek pharmacologic weight-reduction therapy. Fluoxetine-treated and placebo-treated patients did not differ statistically significantly in the incidence of suicidality either during or after discontinuation of therapy.

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 not associated with increased aggression in controlled clinical trials.

A comprehensive meta-analysis was performed to address the possible association of fluoxetine with violence or aggression. Data from the United States Investigational New Drug Clinical Trial Databases for approved and potential indications (depression, obesity, bulimia nervosa, obsessive-compulsive disorder, smoking cessation, alcoholism; n = 3992) were evaluated. Statistically significantly fewer fluoxetine-treated patients (0.15%) than placebo-treated patients (0.65%) experienced events suggestive of aggression (hostility, personality disorder, antisocial reaction). A relative risk analysis indicated that aggression events were four times more likely to occur in placebo-treated patients than in fluoxetine-treated patients. Although the possibility that some rare phenomenon was not detected cannot be excluded, this meta-analysis did not show fluoxetine to be associated with an increased risk of emergence of violent or aggressive behaviour.

Fluoxetine: activating and sedating effects.

Serotonin uptake inhibitors are generally considered activating antidepressants. To assess the 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 the pooled data from two fixed-dose studies 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 treatment-emergent phenomena (p < or = 0.05), but dose-effect relationships differed. Activation rates were relatively stable between 5 mg/day and 40 mg/day, but they increased at 60 mg/day. Sedation rates increased linearly up to 40 mg/day, and then were comparable at 40 mg/day and 60 mg/day. Discontinuations due to 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 at all doses. First occurrences of sedation also peaked early at all doses, but there may have been greater variability in first occurrences of sedation over time in patients receiving lower doses. The persistent occurrences of sedation may decline less over time than the persistent occurrences of activation.

Comorbid anxious signs and symptoms in major depression: impact on functional work capacity and comparative treatment outcomes.

Psychological distress is a driver both of direct and indirect health care costs. Depression compromises functional well-being, such as work productivity. Comorbid anxious features often complicate the recognition of depression and may herald a poor prognosis. We report the results of a cross-sectional naturalistic study to determine the impact of three interventions (no antidepressant, fluoxetine, or tricyclic antidepressant therapy) on relative risk of work days lost in 454 French outpatients with either major or minor depression. Most depressed patients also manifested anxious features (76% with a Hamilton Rating Scale for Anxiety score > or = 12). The presence of anxiety was related to the severity of depression, work absenteeism, and current social instability. Depression severity (Hamilton Rating Scale for Depression score > or = 26, including the contributions of anxious symptoms), psychiatric comorbidity, and psychomotor retardation best predicted continued work absenteeism. Patients with major depression were more likely to receive an antidepressant if they had a past history of depressive episodes and/or previous work disability. Patients with minor depression were less likely to receive drug therapy than patients with major depression, despite their current work disability. Among patients who received fluoxetine or a tricyclic antidepressant for at least 8 weeks, fluoxetine was associated with statistically significantly lower mean anxiety and depression scores and fewer work days missed.

Fluoxetine versus amitriptyline in the treatment of major depression: a multicenter trial.

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.

Fluoxetine: activating and sedating effects at multiple fixed doses.

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.