LY354740, a potent and selective mGlu (metabotropic glutamate receptor)2/3 agonist, has shown efficacy in the treatment of generalized anxiety disorder (GAD). LY544344 is a LY354740 prodrug that ...increases LY354740 bioavailability. This 8-week study was designed to evaluate the efficacy, safety, and tolerability of LY544344 in the treatment of GAD. Participants had a diagnoses of GAD, baseline Hospital Anxiety and Depression Scale anxiety subscale scores > or = 10, and moderate illness severity. Patients were randomized to double-blind treatment with LY544344 16 mg b.i.d. (n = 28), LY544344 8 mg b.i.d. (n = 36), or placebo (n = 44). LY544344 16 mg b.i.d.-treated patients showed significantly greater improvement from baseline in Hamilton Anxiety and Clinical Global Impression-Improvement scores, as well as response and remission rates compared with placebo-treated patients. LY544344 was well tolerated and there were no significant differences in the incidence of treatment-emergent adverse events among the three treatment groups. However, the trial was discontinued early based on findings of convulsions in preclinical studies. In conclusion, the findings of this study support the potential efficacy of mGlu2/3 receptor agonist agents in the treatment of GAD. Additional studies will be needed to further assess the toxicological and clinical profile of LY354740/LY544344.
Existing obesity therapies are limited by safety concerns and modest efficacy reflecting a weight loss plateau. Here, we explore combination therapy with bupropion (BUP), a putative stimulator of ...melanocortin pathways, and an opioid antagonist, naltrexone (NAL), to antagonize an inhibitory feedback loop that limits sustained weight reduction. In vitro electrophysiologic experiments were conducted to determine the extent to which BUP+NAL stimulated hypothalamic pro‐opiomelanocortin (POMC) neurons in mouse brain. A subsequent study further characterized the effect of combination BUP+NAL treatment on food intake in lean and obese mice. Finally, a randomized, blinded, placebo‐controlled trial in obese adult subjects was conducted. Randomization included: BUP (300 mg) + NAL (50 mg), BUP (300 mg) + placebo (P), NAL (50 mg) + P or P+P for up to 24 weeks. BUP+NAL stimulated murine POMC neurons in vitro and caused a greater reduction in acute food intake than either monotherapy, an effect consistent with synergism. Combined BUP+NAL provided sustained weight loss without evidence of an efficacy plateau through 24 weeks of treatment. BUP+NAL completers diverged from NAL+P (P < 0.01) and P+P (P < 0.001) at week 16 and from BUP+P by week 24 (P < 0.05). The combination was also well tolerated. Translational studies indicated that BUP+NAL therapy produced synergistic weight loss which exceeded either BUP or NAL alone. These results supported the hypothesis that NAL, through blockade of β‐endorphin mediated POMC autoinhibition, prevents the classic weight loss plateau observed with monotherapies such as BUP. This novel treatment approach (BUP+NAL) holds promise for the treatment of obesity.
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.
OBJECTIVE: The effect of antipsychotic medication on neurocognitive function remains controversial, especially since most previous work has compared the effects of novel antipsychotic medications ...with those of high doses of conventional medications. This study compares the neurocognitive effects of olanzapine and low doses of haloperidol in patients with first-episode psychosis. METHOD: Patients with a first episode of schizophrenia, schizoaffective disorder, or schizophreniform disorder (N=167) were randomly assigned to double-blind treatment with olanzapine (mean modal dose= 9.63 mg day) or haloperidol (mean modal dose=4.60 mg day) for the 12-week acute phase of a 2-year study. The patients were assessed with a battery of neurocognitive tests at baseline and 12 weeks after beginning treatment. RESULTS: An unweighted neurocognitive composite score, composed of measures of verbal fluency, motor functions, working memory, verbal memory, and vigilance, improved significantly with both haloperidol and olanzapine treatment (effect sizes of 0.20 and 0.36, respectively, no significant difference between groups). A weighted composite score developed from a principal-component analysis of the same measures improved to a significantly greater degree with olanzapine, compared with haloperidol. Anticholinergic use, extrapyramidal symptoms, and estimated IQ had little effect on the statistical differentiation of the medications, although duration of illness had a modest effect. The correlations of cognitive improvement with changes in clinical characteristics and with side effects of treatment were significant for patients who received haloperidol but not for patients who received olanzapine. CONCLUSIONS: Olanzapine has a beneficial effect on neurocognitive function in patients with a first episode of psychosis. However, in a comparison of the effects of olanzapine and low doses of haloperidol, the difference in benefit is small.
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.
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.
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).
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.
This 8-week, double-blind, multicenter study was undertaken to replicate, in a larger sample of patients with treatment-resistant major depressive disorder (MDD; DSM-IV criteria), the results of a ...pilot study of the olanzapine/fluoxetine combination.
The study was begun in August 1999. The primary entry criterion was a history of failure to respond to a selective serotonin reuptake inhibitor (SSRI). Patients (N = 500) who subsequently failed to respond to nortriptyline during an open-label lead-in phase were randomly assigned to 1 of 4 treatment groups: olanzapine (6-12 mg/day) plus fluoxetine (25-50 mg/day) combination, olanzapine (6-12 mg/day), fluoxetine (25-50 mg/day), or nortriptyline (25-175 mg/day). The primary outcome measure was baseline-to-endpoint mean change in score on the Montgomery-Asberg Depression Rating Scale (MADRS).
At the 8-week study endpoint, MADRS total scores decreased by a mean 8.7 points from baseline (28.5) with the olanzapine/fluoxetine combination, 7.0 points from baseline (28.4) with olanzapine (p = .08), 8.5 points from baseline (28.4) with fluoxetine (p = .84), and 7.5 points from baseline (28.8) with nortriptyline (p = .30), with no significant differences among the therapies. The olanzapine/fluoxetine combination was associated with significantly (p < or = .05) greater improvement (decrease) in MADRS scores than olanzapine at weeks 2, 4, 6, and 7; than fluoxetine at weeks 2 through 5; and than nortriptyline at weeks 1 through 4. A post hoc analysis of a subgroup of patients who had an SSRI treatment failure during their current MDD episode (N = 314) revealed that the olanzapine/fluoxetine combination group had a significantly (p = .005) greater decrease in MADRS scores than the olanzapine group at endpoint. Safety data for the olanzapine/fluoxetine combination were similar to those for its component monotherapies.
The olanzapine/fluoxetine combination did not differ significantly from the other therapies at endpoint, although it demonstrated a more rapid response that was sustained until the end of treatment. The results raised several methodological questions, and recommendations are made regarding the criteria for study entry and randomization.
OBJECTIVE: This international, multicenter double-blind trial was
designed to compare the therapeutic profile of an atypical antipsychotic,
olanzapine, with that of a conventional dopamine D2 ...antagonist,
haloperidol. METHOD: A total of 1,996 patients at 174 sites in Europe and
North America were randomly assigned to treatment with olanzapine (N =
1,336) or haloperidol (N = 660) over 6 weeks. The primary efficacy analysis
involved the mean change from baseline to endpoint in total scores on the
Brief Psychiatric Rating Scale (BPRS). Secondary analyses included
comparisons of the mean change in positive and negative symptoms, comorbid
depression, extrapyramidal symptoms, and overall drug safety. RESULTS:
Olanzapine demonstrated clinical results superior to those of haloperidol
on overall improvement according to the BPRS and on every secondary
measure, including depression. Olanzapine was also associated with
significantly fewer discontinuations of treatment due to lack of drug
efficacy or adverse events. Substantially more olanzapine-treated patients
(66.5%) than haloperidol-treated patients (46.8%) completed 6 weeks of
therapy. Statistically significant advantages of olanzapine treatment were
related to 1) change in negative symptoms, 2) extrapyramidal symptom
profile, 3) effect on prolactin levels, and 4) response rate. CONCLUSIONS:
Olanzapine shows a superior and broader spectrum of efficacy in the
treatment of schizophrenic psychopathology, with a substantially more
favorable safety profile, than haloperidol. It meets several of the
criteria for a novel atypical antipsychotic agent.
•A total of 378 patients with high grade NMIBC received BCG and underwent cystectomy.•A total of 62 patients received additional salvage therapy (ST).•ST was not associated with increased risk of ...adverse pathology at cystectomy.•On multivariable analysis ST was not associated with CSS.•In carefully selected patients ST does not worsen oncologic outcomes.
While numerous current clinical trials are testing novel salvage therapies (ST) for patients with recurrent nonmuscle invasive bladder cancer (NMIBC) after bacillus Calmette-Guérin (BCG), the natural history of this disease state has been poorly defined to date. Herein, we evaluated oncologic outcomes in patients previously treated with BCG and ST who subsequently underwent radical cystectomy (RC).
We identified 378 patients with high-grade NMIBC who received at least one complete induction course of BCG (n = 378) with (n = 62) or without (n = 316) additional ST and who then underwent RC between 2000 and 2018. Oncologic outcomes were compared using the Kaplan-Meier method and Cox proportional hazards models. Sensitivity analyses were conducted stratifying by presenting tumor stage, matched 1:3 for receipt vs. no receipt of ST.
Patients receiving ST were more likely to initially present with CIS (26% vs. 17%) and less likely with T1 disease (34% vs. 50%, P = 0.06) compared to patients not treated with ST. Receipt of ST was not associated with increased risk of adverse pathology (≥pT2 or pN+) at RC (31% vs. 41%, P = 0.14). Likewise, 5-year cancer-specific survival did not significantly differ between groups on univariable Kaplan-Meier analysis (73% for ST and 74% for no ST, P = 0.7). Moreover, on multivariable analysis, receipt of ST was not significantly associated the risk of death from bladder cancer (HR 1.12; 95% CI 0.60–2.09, P = 0.7). Results were unchanged on sensitivity analysis.
These data suggest that, in carefully selected patients, ST following BCG for high grade NMIBC does not compromise oncologic outcomes for patients who ultimately undergo RC.
Using time-lapse maps, we visualized the dynamics of schizophrenia progression, revealing spreading cortical changes that depend on the type of antipsychotic treatment. Dynamic, 4-dimensional models ...of disease progression were created from 4 repeated high-resolution brain magnetic resonance imaging scans of 36 first-episode schizophrenia patients (30 men/6 women; mean age: 24.2 ± 5.1 SD years) randomized to haloperidol (HAL) (n = 15) or olanzapine (OLZ) treatment (n = 21), imaged at baseline, 3, 6, and 12 months (144 scans). Based on surface-based cortical models and point-by-point measures of gray matter volume, we generated time-lapse maps for each treatment. Disease trajectories differed for atypical versus typical neuroleptic drugs. A rapidly advancing parietal-to-frontal deficit trajectory, in HAL-treated patients, mirrored normal cortical maturation but greatly intensified. The disease trajectory advanced even after symptom normalization, involving the frontal cortex within 12 months with typical drug treatment. Areas with fastest tissue loss shifted anteriorly in the first year of psychosis. This trajectory was not seen with OLZ. Whether this association reflects either reduced neurotoxicity or neuroprotection cannot be addressed with neuroimaging; changes may relate to glial rather than neural components. These maps revise current models of schizophrenia progression; due to power limitations, the findings require confirmation in a sample large enough to model group × time interactions.
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.
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.
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.
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.
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