Biomedical subjects

G D Tollefson

Publications and source records attributed to G D Tollefson.

At least 55 records · Page 3Linked to original sources

PubMed1997

Standard olanzapine versus placebo and ineffective-dose olanzapine in the maintenance treatment of schizophrenia.

OBJECTIVE: Two studies compared the efficacy of standard-dose oral olanzapine (5 to 15 mg a day) with placebo and with ineffective-dose olanzapine (1 mg a day) in maintenance therapy of schizophrenia. METHODS: The studies were 46-week double-blind extensions of multicenter studies that assessed the efficacy of olanzapine in the acute treatment of schizophrenia. Subjects were 120 adults who met DSM-III-R criteria for schizophrenia with an acute exacerbation and who had a minimum score of 24 on the Brief Psychiatric Rating Scale, who had responded to acute therapy (defined as at least a 40 percent reduction in the BPRS score from baseline or a score of 18 or less during up to six weeks of treatment), and who were outpatients at their last acute-phase visit. Relapse was defined as hospitalization for psychopathology. Relapse risk was analyzed using Kaplan-Meier survival analysis and life table analysis. Patients who relapsed were discontinued from the studies. RESULTS: In the first study (N = 58), patients in the standard-dose olanzapine group experienced a significantly lower relapse risk (p = .002) over one year than patients treated with placebo. The estimated one-year risk of relapse with olanzapine was 28.6 percent, compared with 69.9 percent with placebo. Results were similar in the second study (N = 62); patients treated with standard-dose olanzapine had a significantly reduced risk of relapse (p = .018) over one year compared with patients treated with ineffective-dose olanzapine. The estimated one-year risks of relapse were 19.6 percent for standard-dose olanzapine and 45.5 percent for ineffective-dose olanzapine. CONCLUSIONS: Olanzapine is superior to placebo and ineffective-dose olanzapine in the maintenance therapy of schizophrenia.

Acute Disease↗

PubMed1997

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.

Adult↗

PubMed1997

Efficacy of olanzapine: an overview of pivotal clinical trials.

Olanzapine is a new "atypical" antipsychotic agent that belongs chemically to the thienobenzodiazepine class. Its relatively greater binding affinity for 5-HT2 compared to D2 receptors makes it similar to the atypical agent clozapine, a serotonin/dopamine antagonist. Four double-blind pivotal studies, which compare olanzapine to placebo and/or haloperidol, are presented. The results suggest that olanzapine is as effective as haloperidol for positive symptoms and more effective than haloperidol for the treatment of the negative symptoms of schizophrenia.

Acute Disease↗

PubMed1997

Safety of olanzapine.

Clinical safety data for treatment of acute schizophrenia with olanzapine, a new atypical antipsychotic agent, are summarized. The primary clinical trial safety database included 2500 patients treated with olanzapine, 810 with haloperidol, and 236 with placebo. The overall discontinuation rate from olanzapine treatment was low. Significant adverse events included somnolence, weight gain, and asymptomatic treatment-emergent transaminase elevation. Minimal parkinsonism and akathisia with rare dystonia were noted. No hematotoxicity was noted. The incidence of seizures and sexual dysfunction was rare.

Acute Disease↗

PubMed1997

Fluoxetine and concomitant centrally acting medication use during clinical trials of depression: the absence of an effect related to agitation and suicidal behavior.

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.

Adolescent↗

PubMed1996

Is there a relationship between baseline and treatment-associated changes in [3H]-IMI platelet binding and clinical response in major depression?

A peripheral model for the central 5-HT neuron is the characterization of platelet imipramine binding. We studied an outpatient major depressive cohort who fulfilled Research Diagnostic Criteria for agitation. After a 1-week placebo lead-in, subjects were blindly randomized to either imipramine (IMI) or fluoxetine (FLU) during an 8-week, double-blind study period. Thirty-three subjects (15 IMI, 18 FLU) provided both baseline and endpoint samples for the platelet [3H]-IMI assay. Depression efficacy was comparable across the two treatments, whereas FLU was significantly more effective in reducing secondary anxiolysis (p = .023). Discontinuations due to an adverse event were significantly more frequent with IMI than FLU (p < .01). Baseline affinity (KD) was mildly predictive of change in the HAMD (r = -.22; p = .07). Whereas baseline to endpoint density (Bmax) changes (delta) were similar for IMI (183 +/- 329 fmol/mg) and FLU (196 +/- 402 fmol/mg), a statistically significant treatment difference in delta KD emerged (IMI -0.005 +/- 0.010 pmol/ml versus FLU 0.008 +/- 0.013 at p = 004). Moreover, the changes in KD and HAMD17 trended to a positive correlation among only the FLU-treated subjects (4 = 0.406, p = .095). The clinical effects of 5-HT-based selective antidepressant may be reflected by dynamic changes in the platelet 5-HT uptake apparatus. These data suggest that the baseline confirmational status of the [3H]-IMI:5-HT transporter may reflect a "capacity" for a treatment response.

Adolescent↗

PubMed1996

Cognitive function in schizophrenic patients.

Cognitive impairment is a relatively frequent aspect of schizophrenia. Deficits are most prominent in tasks involving attention, memory, and executive function. Although some research suggests that deterioration is progressive, these deficits appear to be relatively stable over time. Imaging and biochemical studies show that schizophrenia is characterized by a number of morphological, hemodynamic, and neurochemical abnormalities within systems integrating the cortex, temporal lobes, and various limbic structures. Neurochemical assays suggest that the neurotransmitters serotonin, dopamine, and glutamate play a significant role in the disease-associated decrement. Cognitive impairment in schizophrenia impedes psychosocial performance and eventual reintegration into society and is therefore an especially relevant target in the development of new therapeutic modalities. Atypical agents, such as clozapine and olanzapine, hold special promise in this area.

Antipsychotic Agents↗

PubMed1995

Fluoxetine.

Explore the source record for details and available documents.

Antidepressive Agents, Tricyclic↗

PubMed1995

Efficacy and safety of long-term fluoxetine treatment of obesity--maximizing success.

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.

Double-Blind Method↗

PubMed1995

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.

Aged↗

PubMed1995

Acute effects of fluoxetine versus placebo on functional health and well-being in late-life depression.

In a randomized 6-week trial comparing fluoxetine with placebo, the Medical Outcomes Study 36-Item Short-Form Health Status Survey (SF-36) scales were used to measure the effects of treatment on functional health and well-being among elderly (age > or = 60 years) outpatients with major depression. In the fluoxetine and placebo groups, 261 and 271 patients, respectively, completed the SF-36 before treatment and at Weeks 3 and 6. Compared with national norms for individuals over age 60, study patients before treatment exhibited baseline decrements on the following SF-36 scales: mental health, role limitations due to emotional problems, social functioning, vitality, role limitations due to physical problems, and bodily pain. Analyses of SF-36 changed scores from baseline to Week 6 revealed that the fluoxetine group improved more than the placebo group across all scales. Differences in changes of scores between groups were significant (p < .05), favoring the fluoxetine group for the scales of mental health, role limitations due to emotional problems, physical functioning, and bodily pain. Improvements observed in the fluoxetine group were both clinically and socially significant.

Activities of Daily Living↗

PubMed1995

Predicting response to fluoxetine in geriatric patients with major depression.

No consensus exists regarding whether early response to an antidepressant strongly predicts a good outcome, what is the criterion for early response, or when to measure it. We hypothesized that early response (> or = 20% decrease in HAM-d21) after any of weeks 1, 2, or 3 of fluoxetine treatment of major depression in geriatric outpatients would predict a favorable outcome by week 6 or an earlier endpoint accurately enough for clinical use. We also hypothesized that the week 1, 2, and 3 percent changes in 21-item Hamilton Rating Scale for Depression (HAM-D21) would predict the percent change at week 6 (or endpoint) accurately enough for clinical use. We enrolled 671 elderly outpatients with unipolar DSM-III-R major depression in a double-blind, placebo-controlled trial of fluoxetine, 20 mg/day. For analysis, fluoxetine-treated patients were randomly divided into a development set (N = 154) for a preliminary test of our criteria and a validation set (N = 181) to validate the development data set's results. Early responders at weeks 1, 2, and 3 were statistically significantly more likely to experience marked improvement or remission than those lacking early response. However, at week 3, this criterion correctly classified only about three-fourths of patients with regard to marked improvement and only about two-thirds with regard to remission. Moreover, about one-third of patients predicted to experience marked improvement and about three-fifths of those predicted to remit did not. The continuous variable, percent change in HAM-D21, did not produce predictive results of any greater clinical utility. We believe that the sensitivity, specificity, false-positive rate, false-negative rate, and kappa of outcome predictions all should be reported in future studies. Without a full set of descriptive statistics, clinicians can be misled by statistically significant results.

Aged↗

PubMed1994

Inhibitor of antagonist binding to the muscarinic receptor is elevated in Alzheimer's brain.

The 100,000 x g supernatant fraction of human brain contains endogenous inhibitors of antagonist binding to the muscarinic receptor. Significantly greater inhibition was observed with Alzheimer's than non-demented control supernatant fractions. Low molecular weight inhibitor was separated from larger inhibitor species by membrane dialysis (3,500 dalton cut-off). The activity of low molecular weight inhibitor was greatly increased by sulfhydryl reducing agents. While the low molecular weight inhibitor was stable to heat, acid and base for short time periods (< 20 min), it was inactivated by acid hydrolysis (50% loss after 16 h, 100% loss after 96 h). The low molecular weight inhibitor activity is elevated approximately three-fold in Alzheimer's brain. The low molecular weight inhibitor from Alzheimer's brain was found to be a non-competitive inhibitor. This is the first report of endogenous inhibitors in human brain of ligand binding to the muscarinic receptor and of increased inhibitor activity in Alzheimer's disease.

Aged↗

PubMed1994

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.

Adolescent↗

PubMed1994

Response patterns of depressed outpatients with and without melancholia: a double-blind, placebo-controlled trial of fluoxetine versus placebo.

Fluoxetine (20 mg/day) and placebo were compared in 89 outpatient men and women with major depression with (n = 52) or without (n = 37) DSM-III-R melancholia in an 8-week double-blind study to determine predictors of treatment response. Fluoxetine was statistically superior to placebo both within the melancholic subtype and in the total patient group (all measures). Response rate and mean decrease in 17-item Hamilton Depression Rating Scale total score approached statistical significance in favor of fluoxetine-treated melancholic patients compared with fluoxetine-treated non-melancholic patients. There were no statistically significant differences between fluoxetine-treated and placebo-treated non-melancholic patients. Results support DSM-III-R melancholia as a predictor of antidepressant response.

Adolescent↗

PubMed1994

How long to onset of antidepressant action: a meta-analysis of patients treated with fluoxetine or placebo.

The onset of action of antidepressant medications is commonly believed to require three or more weeks based on clinical observation and corollary receptor-based hypotheses. However, this is not congruent with early published observations with the tricyclic antidepressants and has been recently challenged. Time to response has implications for treatment compliance, dose adjustment, patient well-being, and the associated economic costs of depression. Weekly improvement on the 21-item Hamilton Depression Rating Scale (HAMD21) from baseline and time to response for fluoxetine- and placebo-treated patients were compared. Data from six double-blind clinical trials of 6-7 weeks' duration, in which 1447 patients with DSM-III-R major depression had been randomly allocated to fluoxetine (n = 962) or placebo (n = 485), were pooled. Analysis of variance was used to evaluate HAMD21 improvement and the Kaplan-Meier estimate was used to evaluate time to response (> or = 50% improvement in HAMD21). Improvement in HAMD21 was statistically significantly greater for fluoxetine than placebo beginning at Week 1 and continuing throughout all weeks of therapy. However, Week 1 and 2 results varied among the individual studies. HAMD factors of cognition and psychomotor status revealed the most rapid changes for fluoxetine-treated compared with placebo-treated patients. The probability of achieving a clinical response, defined as a HAMD21 score reduction from baseline of at least 50%, was similar for both fluoxetine (0.043) and placebo (0.049) at the end of Week 1. However, by Week 2 and thereafter the probability of a response was greater for fluoxetine than placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Cognition↗

PubMed1994

Is baseline agitation a relative contraindication for a selective serotonin reuptake inhibitor: a comparative trial of fluoxetine versus imipramine.

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.

Adolescent↗

PubMed1994

Continuation treatment of OCD: double-blind and open-label experience with fluoxetine.

Recent advances in the pharmacotherapy of obsessive compulsive disorder (OCD) have led to a significant reduction in suffering and a return to productive living for many patients previously considered refractory to treatment. However, OCD can be a chronic disorder that significantly detracts from an individual's well-being. Potent inhibitors of 5-hydroxytryptamine (5-HT) reuptake have emerged as the first-line choice in the pharmacotherapy of OCD. These members of the therapeutic armamentarium for OCD, while associated with acute symptomatic improvement, have not been extensively studied during continuation therapy. In this study, 274 primary OCD subjects completed a 13-week, double-blind, placebo-controlled trial of three fixed doses of fluoxetine. Treatment responders (n = 76) continued their blinded treatment, whereas acute fixed-dose nonresponders began an open-label trial on their maximally tolerated dose (up to 80 mg daily) for 24 weeks. Responders maintained their acute treatment gains; in addition, all three doses of fluoxetine (20, 40, and 60 mg) were associated with further Y-BOCS improvement over the 24-week extension. Fluoxetine 60 mg achieved a statistically significantly greater reduction in Y-BOCS than placebo during the continuation. Open-label study subjects (n = 198) benefited from dose titration, with two thirds achieving a clinical response during the subsequent 24 weeks. Fluoxetine was well tolerated during both 24-week continuation periods. Only 4 (5.7%) of 70 subjects treated with fluoxetine in the responder extension terminated early due to an adverse event. The open-label extension, fluoxetine (to 80 mg), also demonstrated a low rate of adverse events; the profile of events was consistent with the extensive fluoxetine experience in other clinical populations. In conclusion, fluoxetine continuation treatment in OCD was associated with a maintained/improved symptomatic profile in most cases. Further dose titration improved the outcome of many acute, fixed-dose nonresponders. Continuation treatment with fluoxetine appeared to be well tolerated with few late-emergent adverse events.

Adolescent↗