Biomedical subjects

G D Tollefson

Publications and source records attributed to G D Tollefson.

At least 19 recordsLinked to original sources

PubMed2001

No gender differences in placebo responses of patients with major depressive disorder.

BACKGROUND: This study was designed to compare placebo responses in men and women. METHODS: Data for 501 women and 375 men with major depressive disorder treated with placebo from seven investigational randomized double-blind trials comparing fluoxetine with placebo were analyzed. Changes in major depressive disorder symptoms with placebo administration were measured as changes in total Hamilton Depression Rating Scale scores and adverse (nocebo) effects were measured by comparing treatment-emergent signs and symptoms. RESULTS: Both women and men with major depressive disorder showed significant symptomatic improvement following placebo administration, similar in magnitude and time course of response. Women on placebo reported slightly more nocebo effects than men. CONCLUSIONS: The finding that women and men with major depressive disorder demonstrated a similar therapeutic outcome after placebo administration suggests that gender is not a predictor of placebo response.

Adult↗

PubMed2001

Double-blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine.

BACKGROUND: The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptic drugs is a major challenge. Clozapine has been one treatment option; however, it is not universally effective and is limited in its use by safety concerns. With the introduction of newer agents, their performance relative to clozapine is of great clinical interest. METHODS: The primary objective of this study was to evaluate the efficacy and safety of olanzapine versus clozapine among treatment resistant DSM-IV schizophrenic patients. The study was primarily designed to demonstrate the "noninferiority" of olanzapine compared to clozapine after 18 weeks of double-blind treatment. Conclusions were based on the one-sided lower 95% confidence limit about the treatment effect observed from the primary efficacy variable (Positive and Negative Syndrome Scale [PANSS] Total). RESULTS: Mean changes from baseline to end point in PANSS Total score, using a last observation carried forward technique, showed that both agents were comparably effective in neuroleptic resistant patients, i.e., demonstrated the "noninferiority" of olanzapine when compared to clozapine. Overall, significantly fewer olanzapine-treated patients (4%) discontinued for an adverse event than their clozapine-treated (14%) counterparts (p =.022). Among spontaneously reported adverse events, increased salivation, constipation, dizziness, and nausea were reported significantly more often among clozapine-treated patients, whereas only dry mouth was reported more often among olanzapine-treated patients. CONCLUSIONS: Olanzapine was demonstrated to be noninferior to clozapine and better tolerated among resistant schizophrenic patients clinically eligible for treatment with clozapine.

Adult↗

PubMed2001

The double-blind variable placebo lead-in period: results from two antidepressant clinical trials.

The 1-week single-blind placebo lead-in has long been a standard in double-blind psychopharmacology clinical trials. Although a lead-in period is often necessary (e.g., to receive laboratory results before randomization), some authors have demonstrated that the standard single-blind placebo lead-in's performance was similar to having a lead-in in which placebo was not administered. The single-blind placebo lead-in did not decrease postrandomization placebo response, nor did it increase drug-placebo differences. To eliminate a higher percentage of placebo responders before randomization and to reduce potential biases in baseline ratings, the authors designed and implemented two depression studies with a double-blind variable placebo lead-in period. In these designs, both the patients and personnel at the investigative sites were blinded to the length of the placebo lead-in period and the start of the active treatment period. Approximately 28% of the patients in the double-blind placebo lead-in studies met criteria to be placebo lead-in responders, as compared with fewer than 10% from two single-blind placebo lead-in studies conducted in a similar time frame. Although all patients continued in the study (including placebo lead-in responders), the primary efficacy analysis prospectively excluded double-blind placebo lead-in responders. Analysis of postrandomization changes revealed that double-blind placebo lead-in responders, even when continuing to receive placebo treatment, maintained their response. At the study endpoint, these placebo lead-in responders had significantly lower severity scores than their counterparts who were not lead-in responders. The prospective removal of lead-in responders thus resulted in an increase in mean endpoint placebo group severity scores. This resulted in an increased drug-placebo treatment difference in one of the two studies but had no effect on the treatment difference in the other study.

Antidepressive Agents↗

PubMed2001

A novel augmentation strategy for treating resistant major depression.

OBJECTIVE: Treatment-resistant depression is a significant public health concern; drug switching or augmentation often produce limited results. The authors hypothesized that fluoxetine could be augmented with olanzapine to successfully treat resistant depression. METHOD: An 8-week double-blind study was conducted with 28 patients who were diagnosed with recurrent, nonbipolar, treatment-resistant depression without psychotic features. Subjects were randomly assigned to one of three groups: olanzapine plus placebo, fluoxetine plus placebo, or olanzapine plus fluoxetine. RESULTS: Fluoxetine monotherapy produced minimal improvement on various scales that rate severity of depression. The benefits of olanzapine monotherapy were modest. Olanzapine plus fluoxetine produced significantly greater improvement than either monotherapy on one measure and significantly greater improvement than olanzapine monotherapy on the other measures after 1 week. There were no significant differences between treatment groups on extrapyramidal measures nor significant adverse drug interactions. CONCLUSIONS: Olanzapine plus fluoxetine demonstrated superior efficacy for treating resistant depression compared to either agent alone.

Ambulatory Care↗

PubMed2001

Factors influencing acute weight change in patients with schizophrenia treated with olanzapine, haloperidol, or risperidone.

OBJECTIVE: Clinical factors predicting weight change in patients with schizophrenia and related disorders during acute treatment with the antipsychotic drugs olanzapine, risperidone, and haloperidol were sought through retrospective analyses. METHOD: Six-week body-weight data from 2 trials, study 1 comparing olanzapine and haloperidol (N = 1,369) and study 2 olanzapine and risperidone (N = 268), were analyzed. Effects of 8 clinically relevant covariates--therapy, clinical outcome (Brief Psychiatric Rating Scale), baseline body mass index (BBMI), increased appetite, age, gender, race, and dose--on weight were compared. RESULTS: In study 1, olanzapine (vs. haloperidol) therapy, better clinical outcome, lower BBMI, and nonwhite race significantly affected weight gain. Effects of increased appetite and male gender on weight gain were significant for olanzapine but not for haloperidol. In study 2, better clinical outcome, lower BBMI, and younger age significantly affected weight gain. Increased appetite was more frequent during olanzapine treatment than during haloperidol, but not significantly different from risperidone. Significant differences in effect on weight change were found between olanzapine and haloperidol but not between olanzapine and risperidone. No evidence was found that lower antipsychotic drug doses were associated with lower weight gain. CONCLUSION: This report identifies predictive factors of acute weight change in patients with schizophrenia. Similar factors across antipsychotic drugs in predicting greater weight gain included better clinical outcome, low BBMI, and nonwhite race. Factors differing between conventional (haloperidol) and atypical (olanzapine) agents included increased appetite and gender. Choice of atypical antipsychotic drug (olanzapine vs. risperidone) was of minor importance with regard to influence on acute weight gain.

Adult↗

PubMed2001

Evidence for the effectiveness of olanzapine among patients nonresponsive and/or intolerant to risperidone.

BACKGROUND: This multicenter, open-label study evaluated the efficacy and safety of olanzapine in patients with schizophrenia who had been nonresponsive or intolerant to a course of risperidone (mean duration of risperidone treatment = 46.3 days). METHOD: A total of 34 patients with DSM-III-R and ICD-9 schizophrenia entered this trial. Twenty-five patients were nonresponsive to previous risperidone treatment, 6 patients were intolerant to the risperidone treatment, and 3 patients listed both reasons for discontinuation of risperidone. Patients were treated across a dose range of 5 to 25 mg/day of olanzapine. The primary efficacy variable was baseline to endpoint change in Positive and Negative Syndrome Scale (PANSS) score. Safety was assessed using the Clinical Global Impressions-Severity of Illness scale. RESULTS: Improvement from baseline PANSS score (mean +/- SD PANSS score = 119.4 +/- 26.9) was evident at the week-6 midpoint (-22.2 +/- 19.5) and at the week-14 endpoint (-28.7 +/- 22.3). On average, severity ratings were reduced from baseline by 25% after 14 weeks of olanzapine therapy. Twenty olanzapine-treated patients (58.8%) achieved the a priori-defined response criterion of > or = 20% reduction in PANSS total score. Among patients who met the response criterion, 50% (10/20) had done so by the fourth week. These clinical improvements occurred across a broad range of symptom domains and included reductions in PANSS positive, negative, general psychopathology, and mood subscores. No statistically significant differences were found on any efficacy measure at any visit between the patients who were nonresponsive to risperidone compared with those who were intolerant to risperidone. Olanzapine was well tolerated, with no subject discontinuing early owing to an intolerable adverse event that could be conclusively linked to olanzapine. CONCLUSION: The results of this open-label study suggest that olanzapine may be an effective alternative for schizophrenic patients who are nonresponsive and/or intolerant to risperidone treatment. Moreover, the results underscore the differential pharmacology that exists among the newer antipsychotic agents.

Adult↗

PubMed2001

Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia.

BACKGROUND: Weight change and the weight-related health factors of nonfasting serum glucose, serum cholesterol, and diastolic blood pressure levels were analyzed in patients with DSM-III-R schizophrenia and related disorders who received treatment with olanzapine for up to 3 years, and comparisons were made to patients treated with haloperidol. Baseline body mass index (BBMI; kg/m2) and dose (mg/day) were investigated as predictors of long-term weight change experienced during olanzapine treatment. METHOD: This analysis retrospectively examined 573 patients receiving olanzapine and 103 patients receiving haloperidol for 39 weeks or more from a study of 1,996 patients randomly assigned 2:1 to either olanzapine, 5 to 20 mg/day, or haloperidol, 5 to 20 mg/day. After 6 weeks of acute therapy, patients continued for 1 year or more with either double-blind or open-label olanzapine therapy or double-blind haloperidol therapy. RESULTS: Mean weight gain for olanzapine-treated patients observed for a median of 2.54 years trended toward a plateau after the first 39 weeks of treatment with a last-observation-carried-forward mean weight change of 6.26 kg (13.8 lb) and a median of 5.90 kg (13.0 lb). This was significantly higher than that for haloperidol-treated patients, whose mean weight gain was 0.69 kg (1.5 lb) after 1.15 years (p < .001). Patients with higher BBMI (> 27.6) gained significantly less weight during treatment with olanzapine than their lighter counterparts (BBMI < 27.6) (p < .001). The effect of olanzapine dose on weight was not significant (p > or = . 183). Median serum glucose at endpoint was not significantly associated (p = .096) with weight change for olanzapine. Median serum cholesterol and diastolic blood pressure for olanzapine-treated patients at endpoint showed a relationship with weight change that was statistically (p < or = .001) but not clinically significant. The difference in incidence of elevated serum glucose, cholesterol, or diastolic blood pressure between olanzapine and haloperidol therapy groups was not different (p > .05). CONCLUSION: Mean weight gain during olanzapine treatment trended toward a plateau after the initial 39 weeks of treatment with no further significant gain out to 3 years. Higher BBMI was predictive of a lower long-term weight gain, while dose was not a significant predictor of greater longer term weight change. The relationship between weight change and glucose was not statistically significant. The association between weight change and changes in cholesterol as well as changes in diastolic blood pressure was statistically significant but not considered clinically relevant based on the ranges observed.

Adult↗

PubMed2000

Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group.

BACKGROUND: Patients with Alzheimer disease (AD) commonly exhibit psychosis and behavioral disturbances that impair patient functioning, create caregiver distress, and lead to institutionalization. This study was conducted to assess the efficacy and safety of olanzapine in treating psychosis and/or agitation/aggression in patients with AD. METHODS: A multicenter, double-blind, placebo-controlled, 6-week study was conducted in 206 elderly US nursing home residents with AD who exhibited psychotic and/or behavioral symptoms. Patients were randomly assigned to placebo or a fixed dose of 5, 10, or 15 mg/d of olanzapine. The primary efficacy measure was the sum of the Agitation/Aggression, Hallucinations, and Delusions items (Core Total) of the Neuropsychiatric Inventory-Nursing Home version. RESULTS: Low-dose olanzapine (5 and 10 mg/d) produced significant improvement compared with placebo on the Core Total (-7.6 vs -3.7 [P<.001] and -6.1 vs -3. 7 [P =.006], respectively). Core Total improvement with olanzapine, 15 mg/d, was not significantly greater than placebo. The Occupational Disruptiveness score, reflecting the impact of patients' psychosis and behavioral disturbances on the caregiver, was significantly reduced in the 5-mg/d olanzapine group compared with placebo (-2.7 vs -1.5; P =.008). Somnolence was significantly more common among patients receiving olanzapine (25.0%-35.8%), and gait disturbance occurred in those receiving 5 or 15 mg/d (19.6% and 17.0%, respectively). No significant cognitive impairment, increase in extrapyramidal symptoms, or central anticholinergic effects were found at any olanzapine dose relative to placebo. CONCLUSION: Low-dose olanzapine (5 and 10 mg/d) was significantly superior to placebo and well tolerated in treating agitation/aggression and psychosis in this population of patients with AD.

Aged↗

PubMed2000

Neuropsychological change in early phase schizophrenia during 12 months of treatment with olanzapine, risperidone, or haloperidol. The Canadian Collaborative Group for research in schizophrenia.

BACKGROUND: The purpose of this investigation was to test the efficacy of novel antipsychotic medications in the treatment of cognitive impairment in early phase schizophrenia. METHODS: Sixty-five patients in this multicenter double-blind study were randomly assigned to olanzapine (5-20 mg), risperidone (4-10 mg), or haloperidol (5-20 mg). Standard measures of clinical and motor syndromes were administered, as well as a comprehensive battery of tests to assess (1) motor skills, (2) attention span, (3) verbal fluency and reasoning, (4) nonverbal fluency and construction, (5) executive skills, and (6) immediate recall at baseline and after 6, 30, and 54 weeks of treatment. RESULTS: The general cognitive index derived from the 6 domain scores revealed a significantly greater benefit from treatment with olanzapine relative to haloperidol and olanzapine relative to risperidone, but no significant difference was shown between risperidone and haloperidol. The improvement related to olanzapine was apparent after 6 weeks and enhanced after 30 and 54 weeks of treatment. Exploratory within-group analyses of the 6 cognitive domains after a conservative Bonferroni adjustment revealed a significant improvement with olanzapine only on the immediate recall domain, and similar analyses of the 17 individual tests revealed a significant improvement with olanzapine only on the Hooper Visual Organization Test. CONCLUSIONS: These data suggest that olanzapine has some superior cognitive benefits relative to haloperidol and risperidone. A larger sample replication study is necessary to confirm and generalize the observations of this study and begin evaluation of the implications of this change to cerebral function and quality of life for people with schizophrenia.

Adolescent↗

PubMed2000

Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzipine HGGW Study Group.

BACKGROUND: We compared the efficacy and safety of olanzapine vs placebo for the treatment of acute bipolar mania. METHODS: Four-week, randomized, double-blind, parallel study. A total of 115 patients with a DSM-IV diagnosis of bipolar disorder, manic or mixed, were randomized to olanzapine, 5 to 20 mg/d (n = 55), or placebo (n = 60). The primary efficacy measure was the Young-Mania Rating Scale (Y-MRS) total score. Response and euthymia were defined, a priori, as at least a 50% improvement from baseline to end point and as a score of no less than 12 at end point in the Y-MRS total score, respectively. Safety was assessed using adverse events, Extrapyramidal Symptom (EPS) rating scales, laboratory values, electrocardiograms, vital signs, and weight change. RESULTS: Olanzapine-treated patients demonstrated a statistically significant greater mean (+/- SD) improvement in Y-MRS total score than placebo-treated patients (-14.8 +/- 12.5 and -8.1 +/- 12.7, respectively; P<.001), which was evident at the first postbaseline observation 1 week after randomization and was maintained throughout the study (last observation carried forward). Olanzapine-treated patients demonstrated a higher rate of response (65% vs 43%, respectively; P =.02) and euthymia (61% vs 36%, respectively; P =. 01) than placebo-treated patients. There were no statistically significant differences in EPSs between groups. However, olanzapine-treated patients had a statistically significant greater mean (+/- SD) weight gain than placebo-treated patients (2.1 +/- 2.8 vs 0.45 +/- 2.3 kg, respectively) and also experienced more treatment-emergent somnolence (21 patients [38.2%] vs 5 [8.3% ], respectively). CONCLUSION: Olanzapine demonstrated greater efficacy than placebo in the treatment of acute bipolar mania and was generally well tolerated.

Acute Disease↗

PubMed2000

The effectiveness of olanzapine in treatment-refractory schizophrenia when patients are nonresponsive to or unable to tolerate clozapine.

OBJECTIVE: This multicenter, open-label study was designed to assess the efficacy and tolerability of olanzapine in patients with chronic schizophrenia who are resistant to therapy with classic neuroleptic agents and are either not responsive to or unable to tolerate clozapine. METHODS: Patients received olanzapine orally once daily for 18 weeks at doses ranging from 5 to 25 mg. The primary efficacy measure was change in the total score on the Positive and Negative Syndrome Scale (PANSS) from baseline to end point. Secondary efficacy measures were the total score on the Brief Psychiatric Rating Scale (BPRS); the PANSS positive, negative, general psychopathology, and mood subscores; and the Clinical Global Impression improvement score. Also recorded were spontaneously reported adverse events; extrapyramidal symptoms (assessed by the Abnormal Involuntary Movement Scale, Simpson-Angus Scale, and Barnes Akathisia Scale); vital signs; and clinical laboratory test results. RESULTS: Forty-eight patients were treated with olanzapine; of these, 45 were assessable over the full 18-week study period. Total scores on the PANSS and BPRS were reduced from baseline by an average of 17.7 (14.2%) and 9.8 points (20.2%), respectively. Eighteen patients (40.0%) experienced a treatment response, defined as a reduction in PANSS total score of > or = 20%. A total of 25 patients (55.6%) achieved a similar reduction in BPRS total score. Significant reductions were seen in both the positive and negative symptom scores on the PANSS (P < 0.001). Olanzapine was well tolerated, with minimal treatment-emergent adverse events or clinically relevant changes in vital signs or clinical laboratory test results. No clinically significant blood dyscrasias were observed in olanzapine-treated patients, including those who had discontinued clozapine because of treatment-associated leukopenia or neutropenia. CONCLUSION: The results of this study suggest that olanzapine may be of benefit in patients who are refractory to or unable to tolerate clozapine.

Antipsychotic Agents↗

PubMed2000

Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex.

To understand the mechanism of the clinical efficacy of olanzapine and fluoxetine combination therapy for treatment-resistant depression (TRD), we studied the effects of olanzapine and other antipsychotics in combination with the selective serotonin uptake inhibitors fluoxetine or sertraline on neurotransmitter release in rat prefrontal cortex (PFC) using microdialysis. The combination of olanzapine and fluoxetine produced robust, sustained increases of extracellular levels of dopamine ([DA](ex)) and norepinephrine ([NE](ex)) up to 361 +/- 28% and 272 +/- 16% of the baseline, respectively, which were significantly greater than either drug alone. This combination produced a slightly smaller increase of serotonin ([5-HT](ex)) than fluoxetine alone. The combination of clozapine or risperidone with fluoxetine produced less robust and persistent increases of [DA](ex) and [NE](ex). The combination of haloperidol or MDL 100907 with fluoxetine did not increase the monoamines more than fluoxetine alone. Olanzapine plus sertraline combination increased only [DA](ex). Therefore, the large, sustained increase of [DA](ex), [NE](ex), and [5-HT](ex) in PFC after olanzapine-fluoxetine treatment was unique and may contribute to the profound antidepressive effect of the olanzapine and fluoxetine therapy in TRD.

Animals↗

PubMed2000

Beneficial effect of olanzapine in schizophrenic patients with obsessive-compulsive symptoms.

Some studies suggest that obsessive-compulsive symptoms may be common (7.8-46%) in schizophrenic patients and seem to be poorly responsive to drug therapy. Conventional neuroleptics are of limited value, but adjunctive anti-obsessive agents (clomipramine, fluvoxamine) may be an option. Although novel atypical antipsychotics (clozapine, risperidone) reportedly aggravate the obsessive-compulsive symptoms, a recent trial has shown that olanzapine did not induce new-onset obsessive-compulsive symptoms in schizophrenic patients. We report our experience with three schizophrenic patients with obsessive-compulsive symptoms who were unsuccessfully treated with various conventional neuroleptics in combination with anti-obsessive agents and subsequently showed resistance or intolerance to clozapine. All of them were switched to olanzapine (10-20 mg/ day). All patients demonstrated a significant improvement in both schizophrenic and obsessive-compulsive symptoms as measured by the Brief Psychiatric Rating Scale (BPRS) and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Within 5-8 weeks of initiation of olanzapine, the BPRS scores of the three patient decreased by 53%, 51% and 48%, and the Y-BOCS scores by 68%, 73% and 85%. Olanzapine was well tolerated. These preliminary results suggest that olanzapine may be a therapeutic option in schizophrenic patients with obsessive-compulsive symptoms.

Adult↗

PubMed2000

Meta-analysis of randomised controlled trials of fluoxetine v. placebo and tricyclic antidepressants in the short-term treatment of major depression.

BACKGROUND: Previous meta-analyses of fluoxetine as an antidepressant have many methodological problems, including diagnosis of major depression, validity of outcome measures and lack of intention-to-treat analyses. AIMS: To provide an estimate of the effect of fluoxetine compared with placebo and tricyclic antidepressants (TCAs), and to investigate reasons for early discontinuation from acute treatment. METHOD: Randomised trials were analysed using both intention-to-treat, efficacy and end-point. RESULTS: Fluoxetine was superior to placebo but effect size was low. In trials comparing fluoxetine v. TCA, the results for all trials and for the USA trials showed a trend in favour of fluoxetine. Those for the non-USA trials showed a trend in favour of TCA. When combined, the results showed that significantly fewer patients on fluoxetine discontinued treatment because of adverse events. CONCLUSION: Fluoxetine is superior to placebo, irrespective of the analytical approach use, whereas the results obtained v. TCAs depend on the approach used. Hence, the results should be interpreted in this light.

Antidepressive Agents, Second-Generation↗

PubMed1999

The course of depressive symptoms in predicting relapse in schizophrenia: a double-blind, randomized comparison of olanzapine and risperidone.

BACKGROUND: Depressive symptoms are common during the course of schizophrenia and may carry prognostic relevance. METHODS: From a 28-week prospective, double-blind, randomized study of olanzapine and risperidone, a post hoc evaluation of changes on the Positive and Negative Syndrome Scale (PANSS) depression cluster (PDC) and the subsequent risk of relapse were analyzed by logistic regression. RESULTS: Olanzapine was associated with a significantly higher categorical rate of improvement on the PANSS depression cluster (> or = 7 points) (p < .05). Although the baseline severity of depressive symptoms was not a significant predictor of relapse, the degree of acute (8-week) mood improvement on the PANSS depression cluster (but neither negative or positive symptom changes) was related to the probability of a subsequent psychotic relapse. Acute mood improvement with olanzapine was inversely related to a nonsignificantly lower risk of relapse. However, an opposite and significant relationship was observed among risperidone-treated subjects. Risperidone-treated subjects with a greater degree of acute mood change were both 3.58 times more likely to relapse than their risperidone counterparts who had experienced less mood improvement (p = .008) and 8.55 times more likely than olanzapine-treated subjects who had had similar mood improvements (p = .001). CONCLUSIONS: These data suggest the underlying pharmacologic differences between the two drugs may bestow different rates of longer-term mood stabilization and relapse prevention. In a second series of analyses, worsening on the PANSS depression cluster in the 4 weeks or less preceding a clinical relapse was a significant prodromal predictor of relapse among all subjects. As a whole, subjects with a worsening on the PDC demonstrated a 1.77 times higher risk of a relapse during the subsequent 4 weeks (p = .001). Among this mood-worsening stratum, risperidone-treated patients were 3.51 times more likely to relapse in those next 4 weeks (p = .005) than their olanzapine counterparts. Future comparative drug studies in this area will further contribute to our understanding of the pathophysiology of mood change and its relationship to psychosis, including clinical relapse and how newer agents may differ in their respective delivery of long-term treatment outcomes.

Adult↗

PubMed1999

Anxious-depressive symptoms in schizophrenia: a new treatment target for pharmacotherapy?

Schizophrenia patients frequently manifest concurrent anxiety and depressive symptoms. Such features exhibit prognostic relevance (i.e. patient morbidity and mortality). Despite this, they remain relatively unstudied and are not universally viewed as therapeutic targets. Conventional neuroleptic agents may not improve these symptoms and may actually worsen them. However, with the introduction of novel pharmacological agents for the treatment of schizophrenia, there is reason to believe that a wider spectrum of symptomatology may be treatment responsive. In this post hoc analysis of the Brief Psychiatric Rating Scale anxiety-depression cluster, olanzapine therapy was associated with a significantly greater baseline-to-end-point improvement in the cluster compared with haloperidol therapy among 1996 randomized, double-blind subjects. Moreover, the olanzapine treatment-effect advantage included both direct (mood symptoms) and indirect (positive, negative, and extrapyramidal symptoms) elements. This study concluded that the novel pharmacology of olanzapine delivered greater therapeutic activity in anxious and depressive symptoms accompanying schizophrenia than did the conventional dopamine D2 antagonist haloperidol.

Antipsychotic Agents↗

PubMed1999

Pilot study of zatosetron (LY277359) maleate, a 5-hydroxytryptamine-3 antagonist, in the treatment of anxiety.

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.

Adult↗

PubMed1999

Controlled, double-blind investigation of the clozapine discontinuation symptoms with conversion to either olanzapine or placebo. The Collaborative Crossover Study Group.

The abrupt appearance of clozapine discontinuation symptoms represents a particularly unique situation that has not been characterized in a double-blind, placebo-controlled trial. A randomized, double-blind comparison of placebo (N = 53) and olanzapine 10 mg (N = 53) for 3 to 5 days following the abrupt discontinuation of clozapine (< 300 mg/day) was carried out. Subjects were assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale of Severity, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Mini-Mental State Evaluation. Subsequently both groups received open-label olanzapine (10-25 mg/day) for an additional 9 weeks. Statistically significantly more placebo-treated (24.5%) than olanzapine-treated (7.5%) patients experienced clozapine discontinuation symptoms (p = 0.017). Core symptoms included delusions, hallucinations, hostility, and paranoid reaction and translated into a significantly higher worsening from baseline on the PANSS total, PANSS General Psychopathology subscale, and MADRS among subjects randomly assigned to receive placebo. After open-label treatment with olanzapine for 9 weeks, both groups were clinically stable, suggesting that the discontinuation symptoms were transient. However, subjects who had been randomly assigned to the 3- to 5-day placebo discontinuation segment achieved somewhat less global clinical improvement. Although a pharmacologic interpretation is speculative, evidence of a clozapine discontinuation syndrome was apparent. In most cases, the direct substitution of a pharmacologically similar agent (olanzapine) prevented the syndrome. Clozapine discontinuation or noncompliance should be considered in the differential assessment of an acutely emergent psychosis. The possibility that subjects who experience a clozapine discontinuation syndrome may take longer or are less likely to clinically restabilize warrants further investigation.

Adult↗