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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.

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 scoresor = 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.

Ongoing discussion of potential benefits and risks of antidepressant treatment with respect to suicidal behaviors includes many ecological, or population-based, correlational studies of temporal or regional trends in suicide rates and rates of usage of modern antidepressants including serotonin-reuptake inhibitors (SRIs). Since this body of research has not been compiled and evaluated, we used computerized literature searching to identify 19 relevant published studies. They yielded heterogeneous findings: only 8/19 found significant inverse correlations between rising sales of modern antidepressants in the 1990 s and falling suicide rates not anticipated in the 1980s. Average reductions in suicide rates in the 1990 s (10.7%) and 1980s (10.0%) differed little in 11 studies with data from both eras. Reduction of suicide rates in the 1990 s was unrelated to geographic region, population size, units of analysis, publication year, or growth in antidepressant usage, but was greater with higher initial suicide rates, in men, and in older persons. In the same decade, suicides rates decreased in only half of 79 large countries. Overall, these findings yield limited and inconsistent support for the hypothesis that increased use of modern antidepressants might limit suicide risk, and no evidence that the risk increased. Suicidal risk is determined by complex factors, including access to clinical services, in general, and more comprehensive treatment of depression, in particular. Overall, as with findings from randomized trials and cohort or case-control studies, evidence of specific antisuicidal effects of antidepressant treatment from ecological analyses remains elusive.

The goal of a non-inferiority study is to test whether a new treatment has at least as much efficacy as an established treatment. The purpose of this non-inferiority study was to compare the speed of onset of antidepressant efficacy for duloxetine (a dual serotonin and norepinephrine reuptake inhibitor) and escitalopram (a selective serotonin reuptake inhibitor).This was a randomized, double-blind, placebo- and active comparator-controlled study, in which patients (or = 18 years) meeting DSM-IV criteria for Major Depressive Disorder (MDD) received duloxetine 60 mg once daily (QD; N = 273), escitalopram 10 mg QD (N = 274), or placebo (N = 137) for 8 weeks. The primary objective was to compare the onset of antidepressant efficacy, by testing the hypothesis that the percentage of duloxetine-treated patients achieving onset criteria at Week 2 was not inferior to that in the escitalopram group.Onset of efficacy was defined as a 20% decrease from baseline on the 17-item Hamilton Rating Scale for Depression (HAMD(17)) Maier subscale that was maintained or exceeded at all subsequent visits.Probabilities of meeting onset criteria at Week 2 for duloxetine- and escitalopram-treated patients were 42.6% versus 35.2%, respectively (treatment difference = 7.4%; 95% confidence interval, -1.3% to 16.2%; p = 0.097). Both drugs showed significant improvement compared with placebo (por = 0.05) on the primary efficacy measure (Maier subscale) at Week 1 and endpoint (Week 8). No differences were found between duloxetine, escitalopram, and placebo rates of remission or response at 8 weeks. Adverse events that occurred significantly more frequently among duloxetine-treated patients when compared with those receiving escitalopram were nausea, dry mouth, vomiting, yawning, and irritability. The rate of discontinuation due to adverse events did not differ significantly between treatment groups.Given the difficulties in constructing appropriate dose comparisons, the results of this study should be interpreted specific to the doses tested and not extrapolated to the drug as a whole. This study employed a fixed-dose design; flexible-dose designs are more likely to find a difference between antidepressants and placebo.In this study, both duloxetine and escitalopram showed significantly greater improvement on the primary efficacy measure than placebo over the 8-week acute treatment period, while no differences were observed between drugs or between drugs and placebo on response and remission rates at 8 weeks. Escitalopram at a starting dose of 10 mg QD was better tolerated than duloxetine at a starting dose of 60 mg QD. This study met its pre-defined primary objective of assessing if duloxetine was non-inferior to escitalopram in antidepressant onset efficacy, and the results show that duloxetine is at least as fast as (non-inferior to) escitalopram.

The novel antipsychotic agent olanzapine (Zyprexa, Eli Lilly and Company) is a thienobenzodiazepine analog marketed for the treatment of schizophrenia. Olanzapine's diverse receptor binding profile and greater affinity for serotonin receptors over dopamine receptors is thought to impart antipsychotic efficacy with a low incidence of serious extrapyramidal symptoms (EPS). With once daily dosing steady-state plasma concentrations reached within approximately 1 week. Olanzapine is extensively metabolized by the liver, is mostly excreted in the urine, and has few drug intractions. In clinical trials, the efficacy of olanzapine for treating schizophrenia is better than placebo and haloperidol and comparable to risperidone. Olanzapine may also ameliorate some comorbid symptoms including negative symptoms, depression, anxiety, substance abuse, and cognitive dysfunction, and it is effective in the long-term maintenance of response, treatment-resistance, and improving quality of life. The overall direct costs are lower with olanzapine treatment compared with haloperidol or risperidone treatment. In clinical trials, olanzapine demonstrates a favorable safety profile. The most frequently reported treatment-emergent adverse events are somnolence, schizophrenic reaction, insomnia, headache, agitation, rhinitis, and weight gain. Significantly fewer EPS (based on formal rating scales) and incidences of tardive dyskinesia have been reported for olanzapine compared with haloperidol. Olanzapine has not been associated with persistent elevations of prolactin above the upper limit of normal nor has it been associated with clinically significant changes in cardiac QTc interval. Fewer incidences of suicide attempts have been reported with olanzapine compared with placebo, haloperidol, or risperidone treatments. There is evidence that olanzapine may be effective in the treatment of mood disorders, psychosis associated with Alzheimer's disease, obsessive-compulsive disorder, pervasive developmental disorders, and delirium. Patients with schizophrenia have been successfully switched from other antipsychotics to olanzapine. In conclusion, olanzapine offers a significantly improved risk-to-benefit profile compared with haloperidol and possibly risperidone, and thus should be considered an important treatment option for schizophrenia and related disorders. SUMMARY Olanzapine is an innovative pharmaceutical product that has been prescribed to more than four million individuals worldwide. Olanzapine has a diverse neurotransmitter receptor binding profile that is similar to clozapine, with selective affinity for the serotonin receptors over the dopamine receptors. In vitro and in vivo preclinical experimentation has provided evidence for the antipsychotic efficacy of olanzapine with a low incidence of serious EPS. In addition, olanzapine has a pharmacokinetic profile that allows for single daily dosing and has minimal metabolic interactions with commonly coadministered medications. Through its distinct pharmacology, olanzapine offers patients a significantly improved risk-benefit profile. Across the diverse series of clinical studies discussed in this review, olanzapine has helped to redefine the expectations for the pharmacotherapy of schizophrenia. Olanzapine (5 to 20 mg/day) has demonstrated an improvement in total psychopathology, which was significantly greater than that seen with placebo or the active comparator, haloperidol. This effect was comprised of at least comparable benefits to haloperidol on positive psychotic symptoms and superior results for the more chronic and disabling features of negative, concurrent anxious and depressive, and cognitive symptoms. This broadened range of treatment-responsive symptoms is complemented by a greater depth of clinical response as well. Given the historical challenge of compliance with the older antipsychotic drugs, it is also noteworthy that these outcomes were achieved with an adverse event discontinuation rate similar to placebo. Compared with conventional antipsychotic agents, the incidence of troublesome EPS or hyperprolactinemia was low. Studies in special populations (i.e., the geriatric patient) appear to confirm this safety profile. Because schizophrenia is a chronic disease, controlled and blinded maintenance studies showing the superiority of olanzapine to placebo or active comparators (haloperidol, risperidone) are also reassuring, especially in the context of the long-term safety experience with olanzapine. In particular, data suggesting a lower incidence of potentially irreversible movement disorders, such as tardive dyskinesia, are striking and of importance to treatment decision makers. Moreover, these advantages appear to translate into improved quality of patient life, increased functional well-being (i.e., return to work), and an overall reduction in the total direct cost of managing schizophrenia. While further studies are ongoing, the data on olanzapine in mood disorders and psychosis associated with Alzheimer's disease are encouraging. Additional studies evaluating olanzapine in nonschizophrenic disorders are awaited. As more “atypical” agents enter the marketplace, head-to-head comparisons are encouraged to properly evaluate the relative merits of each compound. Experience to date tells us that the newer agents to treat psychosis are not all alike. Based on the clinical review in this paper, olanzapine does seem to represent a novel and compelling first-line option for the management of psychotic disorders.

BackgroundSubstantial weight gain is common with many atypical antipsychotics.AimsTo evaluate the extent, time course and predictors of weight gain and its effect on study retention among people with first-episode psychosis treated with olanzapine or haloperidol.MethodSurvival analysis assessed time to potentially clinically significant weight gain (⩾7%) and the effect of weight gain on study retention. Weight gain during the 2-year study was summarised using last-observation-carried-forward (LOCF), observed cases and study completion approaches.ResultsAfter 2 years of treatment, LOCF mean weight gain was 10.2 kg (s.d.=10.1) for olanzapine (n=131) and 4.0 kg (s.d.=7.3) for haloperidol (n=132); observed cases mean weight gain was 15.4 kg (s.d.=10.0) for olanzapine and 7.5 kg (s.d.=9.2) for haloperidol. Change in body mass index was significantly predicted only by treatment group (P< 0.0001).ConclusionsOlanzapine was associated with significantly greater weight gain than haloperidol, with both leading to greater weight gain than previously described.

The purpose of this study was to compare the efficacy and safety of olanzapine (OLZ) monotherapy and an olanzapine/fluoxetine combination (OFC) with placebo (PLA) for unipolar major depression with psychotic features. Under a single protocol, two 8-week, double-blind trials were conducted at 27 sites. Patients (n = 124 trial 1, n = 125 trial 2) were randomized to 1 of 3 treatment groups: OLZ (5 to 20 mg/d), PLA, or OFC (olanzapine 5 to 20 mg/d + fluoxetine 20 to 80 mg/d). The primary outcome measure was the 24-item Hamilton Depression Rating Scale total score. For trial 1, endpoint improvement for the OLZ group (-14.9) was not significantly different from the PLA or OFC groups. The OFC group had significantly greater endpoint improvement (-20.9) than the PLA group (-10.4, P = 0.001); this significant difference was present within 7 days of therapy and maintained at every subsequent visit. The OFC group also had significantly higher response rate (63.6%) than the PLA (28.0%, P = 0.004) or OLZ (34.9%, P = 0.027) groups. For trial 2, there were no significant differences among treatment groups on the 24-item Hamilton Depression Rating Scale total scores or response rates. The combination exhibited a comparable safety profile with OLZ monotherapy and no significant increases in extrapyramidal symptoms compared with placebo. Patients with major depression with psychotic features treated with OLZ monotherapy did not demonstrate significant depressive symptom improvement compared with placebo in either trial; however, an olanzapine/fluoxetine combination was associated with significant improvement compared with placebo in one trial and was well tolerated.

Sustained response to antipsychotic therapy is an important outcome measure for patients with psychotic disorders. Placebo control in studies of relapse prevention contributes valuable information yet provokes much debate. This study, using placebo as a control, evaluated olanzapine's efficacy in preventing a psychotic relapse. Participants were stable minimally symptomatic outpatients with schizophrenia or schizoaffective disorder. The study included 4 phases: (1) 4-day to 9-day screening/evaluation (N = 583), (2) 6-week conversion to open-label olanzapine (N = 493; 10-20 mg/d), (3) 8-week stabilization on olanzapine (N = 458; 10-20 mg/d), and (4) 52-week randomized (2:1), double-blind maintenance with olanzapine (N = 224; 10-20 mg/d) or placebo (N = 102). Primary relapse criteria were clinically significant changes in the Brief Psychiatric Rating Scale (BPRS) positive item cluster or rehospitalization due to positive symptoms. Statistical methodology allowed sequential real-time estimation of efficacy across blinded treatment groups and multiple interim analyses, which permitted study termination when efficacy was significantly different between treatments. A significant between-treatment difference emerged 210 days after first patient randomization to double-blind treatment. Thus, 151 (46.3%) of the randomized patients were discontinued early and 34 (10.4%) of the planned patient enrollment were not required. The olanzapine group had a significantly longer time to relapse (P < 0.0001) than the placebo group. The 6-month cumulative estimated relapse rate (Kaplan-Meier) was 5.5% for olanzapine-treated patients versus 55.2% for placebo-treated patients. The design of this study enabled appropriate statistical testing of the primary hypothesis while minimizing exposure of patients to a less effective treatment than olanzapine. In remitted stabilized patients with schizophrenia or schizoaffective disorder, olanzapine demonstrated a positive benefit-to-risk profile in relapse prevention.

Background: This analysis compares the efficacy of risperidone and olanzapine in controlling negative and positive symptoms of chronic psychosis in older patients. Method: Post hoc assessments were made in a subset of risperidone-treated (N = 19) and olanzapine-treated (N = 20) older patients (aged 50 to 65 years) from a large international, multicenter, parallel, double-blind, 28-week study of patients aged 18 to 65 years (N = 339) randomly assigned to receive risperidone (4-12 mg/day) or olanzapine (10-20 mg/day). Assessments were made using repeated-measures analysis. Results: At both 8 weeks and 28 weeks, the magnitude of changes in Positive and Negative Syndrome Scale (PANSS) positive symptom subscale scores did not differ between treatment groups (8 weeks: risperidone, -6.5; olanzapine, -6.8, p = .866; 28 weeks: risperidone, -6.5; olanzapine, -7.0; p = .804). However, by the 8-week timepoint, olanzapine had reduced PANSS negative subscale scores significantly more than risperidone (-8.8 vs. -4.9, p = .032). By the 28-week endpoint, olanzapine had continued to maintain significantly greater reduction in baseline-to-endpoint PANSS negative scores (-8.1 vs. -3.5, p = .032) and led to significantly greater reduction in scores on the Scale for the Assessment of Negative Symptoms (SANS) dimensions of affective flattening (-5.2 vs. -0.6, p = .033) and alogia (-3.8 vs. -0.3, p = .007). Patients in the olanzapine treatment group also demonstrated numerically greater reduction of both SANS summary (-3.7 vs. -1.0, p = .078) and SANS composite scores (-14.1 vs. -4.1, p = .075). Conclusion: These data demonstrate that, in older patients with schizophrenia and related psychotic disorders, risperidone and olanzapine have approximately equal efficacy in controlling positive symptoms. However, olanzapine appears to be more efficacious in maintaining control over negative symptoms.

Few long-term studies have compared the efficacy and safety of typical and atypical antipsychotic medications directly in patients with a first episode of psychosis who met the criteria for schizophrenia or a related psychotic disorder. This study compared the acute and long-term effectiveness of haloperidol with that of olanzapine in patients with first-episode psychosis in a large, controlled clinical trial.Patients with first-episode psychosis (N=263) were randomly assigned under double-blind conditions to receive haloperidol or olanzapine and were followed for up to 104 weeks. Domains measured included psychopathology, psychosocial variables, neurocognitive functioning, and brain morphology and metabolism. This report presents data from clinical measures of treatment response and safety data from the 12-week acute treatment phase.Haloperidol and olanzapine were associated with substantial and comparable baseline-to-endpoint reductions in symptom severity, which did not differ significantly in last-observation-carried-forward analyses. However, in a mixed-model analysis, olanzapine-treated subjects had significantly greater decreases in symptom severity as measured by the Positive and Negative Syndrome Scale total score and negative and general scales and by the Montgomery-Asberg Depression Rating Scale but not as measured by the Positive and Negative Syndrome Scale positive scale and by the Clinical Global Impression severity rating. Olanzapine-treated patients experienced a lower rate of treatment-emergent parkinsonism and akathisia but had significantly more weight gain, compared with the haloperidol-treated patients. Overall, significantly more olanzapine-treated subjects than haloperidol-treated subjects completed the 12-week acute phase of the study (67% versus 54%).As expected on the basis of previous studies, both olanzapine and haloperidol were effective in the acute reduction of psychopathological symptoms in this group of patients with first-episode psychosis. However, olanzapine had several relative advantages in therapeutic response. Although the nature of adverse events differed between the two agents, retention in the study was greater with olanzapine. Retention in treatment is important in this patient population, given their risk of relapse. Longer-term results are needed to determine whether treatment with atypical antipsychotics results in superior outcomes for a first episode of schizophrenia.

The authors provide a detailed clinical description of minor depression: its symptoms, level of disability, stability, and relationship to patient and family history of major depressive disorder.Rigorous criteria for minor depression, including functional disability, were used to identify 226 individuals for a three-phase treatment study. This report presents data obtained on that study group during the first study phase, a 4-week placebo lead-in period.One hundred sixty-two subjects (72% of the initial study group) remained in the study for 4 weeks and continued to meet criteria for minor depression. Minor depression in these subjects was primarily characterized by mood and cognitive symptoms, not the classical neurovegetative signs and symptoms of depression. Approximately one-third of the subjects with minor depression had a past history of major depressive disorder, and nearly half had a family history of unipolar depressive disorder; however, neither factor affected the severity or quality of minor depressive symptoms.These data suggest that 1) minor depression is not evanescent; 2) minor depression is characterized by mood and cognitive symptoms rather than neurovegetative symptoms; 3) minor depression may occur either independently of a lifetime history of major depressive disorder or as a stage of illness in the course of recurrent unipolar depressive disorder; and 4) depressive disorders should be conceptualized as a continuum of severity.

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.

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 27.6) gained significantly less weight during treatment with olanzapine than their lighter counterparts (BBMI 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 .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.

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.

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.

Depressive symptoms are common during the course of schizophrenia and may carry prognostic relevance.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.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).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.

OBJECTIVE: The primary intent of this study was to compare the efficacy and safety of olanzapine and placebo in the treatment of acute mania. METHOD: The design involved a random-assignment, double-blind, placebo-controlled parallel group study of 3 weeks’ duration. After a 2- to 4-day screening period, qualified patients were assigned to either olanzapine (N=70) or placebo (N=69). Patients began double-blind therapy with either olanzapine, 10 mg, or placebo given once per day. After the first day of treatment, the daily dose could be adjusted upward or downward, as clinically indicated, by one capsule (olanzapine, 5 mg/day) within the allowed range of one to four capsules. The primary efficacy measure in the protocol was defined as a change from baseline to endpoint in total score on the Young Mania Rating Scale. Clinical response was defined a priori as a decrease of 50% or more from baseline in Young Mania Rating Scale total score. RESULTS: The olanzapine group experienced significantly greater mean im...

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.

BackgroundData concerning appropriate treatment in panic disorder following an initial response to acute therapy are limited.AimsTo assess the safety and efficacy of continued fluoxetine treatment following successful acute therapy of panic disorder.MethodPatients who responded to acute fluoxetine treatment were randomised to 24 weeks of continued fluoxetine or placebo.ResultsFluoxetine responders randomised to continue on their acute-phase fluoxetine dose experienced statistically significant improvement in panic attack frequency and phobia rating scale score over 24 weeks of therapy, while those switched to placebo experienced statistically significant worsening in Hamilton Anxiety (HAM–A), Hamilton Depression (HAM–D) and SCL–90–R rating scores.ConclusionsFluoxetine was associated with improved clinical outcomes compared with placebo during continuation therapy.

Olanzapine is a novel antipsychotic agent displaying a unique and pleotrophic pharmacology, which distinguishes it from other existing treatments. Clinical investigations employing olanzapine have demonstrated a number of potential therapeutic advantages in reference not only to placebo but also to contemporary drug standards in the management of psychosis. This paper reviews data on the pharmacokinetics, efficacy and safety of olanzapine, its benefits for quality of life, and economic aspects to assist clinicians in determining where they can usefully employ it.

The purpose of this study was to compare, from the payor perspective, the clinical and economic outcomes of olanzapine to those of haloperidol for the treatment of schizophrenia.Clinical, quality-of-life and resource utilisation data were prospectively collected for US-residing patients with schizophrenia who were participating in a multicentre, randomised, double-blind clinical trial comparing olanzapine and haloperidol. Direct medical costs were estimated by assigning standardised prices (1995 values) to the resource utilisation data.817 patients with schizophrenia who had a baseline Brief Psychiatric Rating Scale score (BPRS)or = 18 (items scored 0 to 6) and/or were no longer tolerating current antipsychotic therapy.Olanzapine 5 to 20 mg/day (n = 551) or haloperidol 5 to 20 mg/day (n = 266) for 6 weeks. Patients showing a predefined level of clinical response entered a 46-week maintenance phase.After acute treatment, BPRS-based clinical improvements were seen in 38 and 27% of olanzapine and haloperidol patients, respectively (p = 0.002). Clinically important improvements on the Quality of Life Scale were achieved during acute treatment in 33% of olanzapine recipients and 25% of haloperidol recipients (p = 0.094). Olanzapine treatment in the acute phase led to significantly lower inpatient ($US5125 vs $US5795, p = 0.038) and outpatient ($US663 vs $US692, p = 0.001) costs, resulting in a significant overall reduction in mean total medical costs of $US388 (p = 0.033). This significant reduction in total costs was found despite olanzapine mean medication costs being significantly greater than haloperidol medication costs ($US326 vs $US15, p0.001). No significant differences in clinical improvement were observed in the maintenance phase. Maintenance phase olanzapine mean total medical costs were $US636 lower than haloperidol total costs (p = 0.128). Although olanzapine medication costs were significantly higher than haloperidol medication costs ($US3461 vs $US95, p0.001), this difference was offset by significantly lower inpatient ($US8322 vs $US10,662, p = 0.044) and outpatient ($US3810 vs $US5473, p = 0.038) costs.In this study, olanzapine treatment was more effective than haloperidol in producing clinical response in the acute phase. In addition, olanzapine treatment led to reductions in inpatient and outpatient costs that more than offset olanzapine's higher medication costs relative to haloperidol.

BackgroundTardive dyskinesia is important in the side-effect profile of antipsychotic medication.AimsThe development of tardive dyskinesia was evaluated in patients treated with double-blind, randomly assigned olanzapine or haloperidol for up to 2.6 years.MethodsTardive dyskinesia was assessed by the Abnormal Involuntary Movement Scale (AIMS) and Research Diagnostic Criteria for Tardive Dyskinesia (RD-TD); it was defined as meeting RD-TD criteria at two consecutive assessments. The risk of tardive dyskinesia, the relative risk, incidence rate, and incidence rate ratio were estimated.ResultsThe relative risk of tardive dyskinesia for the overall follow-up period for haloperidol (n=522) v. olanzapine (n=1192) was 2.66 (95% CI=1.50–4.70). Based on data following the initial six weeks of observation (during which patients underwent medication change and AIMS assessments as frequently as every three days), the one-year risk was 0.52% with olanzapine (n=513) and 7.45% with haloperidol (n=114). The relative risk throughout this follow-up period was 11.37 (95% Cl=2.21–58.60).ConclusionOur results indicated a significantly lower risk of tardive dyskinesia with olanzapine than with haloperidol.

Objective:Although panic attacks account for only a portion of the morbidity of panic disorder and panic attack frequency assessments are unreliable, studies of drug efficacy in panic disorder have generally used reduction in panic attack frequency as the primary measure of improvement. The authors studied the efficacy of fluoxetine treatment in panic disorder and measured the relative contributions of changes in symptoms to overall improvement.Method:Patients with a diagnosis of panic disorder (N=243) were randomly assigned to treatment with 10 or 20 mg/day of fluoxetine or placebo. Primary outcome measures were change in panic attack frequency and clinician-rated Clinical Global Impression improvement scores. Other assessments included a panic attack inventory, clinician-rated and patient-rated versions of the Panic and Phobic Disorder Change Scale, a phobia rating scale, the Hamilton Anxiety Rating Scale, the 21-item Hamilton Depression Rating Scale, and the Sheehan Disability Scale. Correlations were ...

In an era of constrained health care financing, clinicians are increasingly faced with considering the economic consequences in addition to the clinical outcomes associated with initiating a patient on antidepressant therapy. This has increased the demand for health economic studies comparing antidepressant use and associated health care expenditures in clinical practice. These health economics studies have used methods ranging from clinical trials to other types of analyses including prospective naturalistic trials or retrospective studies which may be less familiar to clinicians. Prospective and retrospective health economics studies performed in clinical practice complement the experience gained from clinical trials in assessing antidepressant use and economic outcomes in light of patient and provider behavior within the usual care environment of a complex health care system. Broadly considered, health economic studies of antidepressants have consistently found differences in clinical practice between the tricyclic antidepressants (TCAs) and the selective serotonin reuptake inhibitors (SSRIs) as well as among the SSRIs. These differences relate to the pattern and duration of antidepressant use as well as total direct health care expenditures. Future health economic research studies in clinical practice should focus on the economic consequences of long-term antidepressant use as well as the impact of antidepressant use on indirect costs such as productivity and absenteeism.

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.

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.

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 treatmentemergent 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. (Am J Psychiatry 1997; 154:1248‐1254)

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

A 6-week acute phase of an international 1-year double-blind study was conducted comparing three dose ranges of olanzapine (5 +/- 2.5 mg/day, 10 +/- 2.5 mg/day, and 15 +/- 2.5 mg/day) with a fixed dose of olanzapine (1.0 mg/day) and with a dose range of haloperidol (15 +/- 5 mg/day) in the treatment of 431 patients with schizophrenia. The purpose was to determine whether olanzapine demonstrated a dose-related ability to decrease overall psychopathology with minimal associated extrapyramidal symptoms in patients with schizophrenia. The high-dose olanzapine group showed statistically significantly greater improvement in overall psychopathology based on mean change in the CGI Severity score and statistically significantly greater improvement in positive psychotic symptoms based on mean change in both the BPRS positive score and the PANSS positive score compared with the 1.0-mg/day olanzapine group. Analyses indicated that an increasing dose-response curve was observed across the range of all olanzapine dose groups. Acute extrapyramidal syndromes were reported less frequently among all olanzapine groups compared with the haloperidol group. Endpoint mean change on both the Simpson-Angus Scale and the Barnes Akathisia Scale reflected improvement for all olanzapine treatment groups compared with worsening for the haloperidol group. Olanzapine was associated with weight gain but did not appear to have any clinically meaningful effect on vital signs. Although olanzapine was associated with some increase in prolactin concentrations, increases were transient, occurred less often, and were of lesser magnitude than those observed with haloperidol.

OBJECTIVE The authors investigated whether primary negative symptoms of schizophrenia are enduring or treatment-responsive. METHODS Previously, a double-blind, random-assignment trial of the novel antipsychotic olanzapine (in low, medium, and high dose ranges), placebo, or haloperidol (10-20 mg/day) for 335 schizophrenic inpatients was conducted for up to 52 weeks. Changes in the treatment groups from baseline to endpoint in summary scores on the Scale for the Assessment of Negative Symptoms (SANS) and several secondary measures were compared. This article describes a path analysis to determine to what extent the total treatment effect on negative symptoms was direct or indirect (i.e., mediated by differential effects on positive symptoms, extrapyramidal symptoms, or mood). RESULTS Significantly greater improvement was achieved with high-dose olanzapine than with placebo or haloperidol. Olanzapine had a significantly greater direct effect than placebo on all SANS dimensions except anhedonia-asociality. Olanzapine also demonstrated a significantly greater direct effect than haloperidol on negative symptoms, especially on the dimensions of affective flattening and avolition-apathy. Olanzapine's superior effects were replicated in a subgroup with SANS-defined prominent negative symptoms (N = 116) and a subgroup with a BPRS-defined cross-sectional proxy for the deficit state (N = 117). CONCLUSIONS These results suggest that the negative symptoms of schizophrenia are directly responsive to treatment. The significantly greater direct and indirect effects of olanzapine than of haloperidol on negative symptoms are likely related to olanzapine's pleotrophic pharmacology, which includes dopaminergic, serotonergic, muscarinic, and adrenergic activities. The results contribute to the hypothesis that negative symptoms may be under the influence of several neurotransmitters within one or more neuroanatomic circuits.

Objective: To evaluate the therapeutic effects of selective cholinergic replacement with xanomeline tartrate, an ml and m4 selective muscarinic receptor (mAChR) agonist in patients with probable Alzheimer disease (AD). Design: A 6-month, randomized, double-blind, placebocontrolled, parallel-group trial followed by a 1-month, single-blind, placebo washout. Setting: Outpatients at 17 centers in the United States and Canada. Participants: A total of 343 men and women at least 60 years of age with mild to moderate AD. Interventions: Patients received 75, 150, or 225 mg (low, medium, and high doses) of xanomeline per day or placebo for 6 months. Outcome Measures: Scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change (CIBIC+), the Alzheimer's Disease Symptomatology Scale (ADSS), and the Nurses' Observational Scale for Geriatric Patients (NOSGER). Results: A significant treatment effect existed for ADAS-Cog (high dose vs placebo;P≤.05), and CIBIC+ (high dose vs placebo;P≤.02). Treatment Emergent Signs and Symptoms analysis of the ADSS, which assesses behavioral symptoms in patients with AD, disclosed significant (P≤.002) dose-dependent reductions in vocal Out-bursts, bursts, suspiciousness, delusions, agitation, and hallucinations. On end-point analysis, NOSGER, which assesses memory, instrumental activities of daily living, self-care, mood, social behavior, and disturbing behavior in the elderly, also showed a significant dose-response relationship (P≤.02). In the high-dose arm, 52% of patients discontinued treatment because of adverse events; dose-dependent adverse events were predominantly gastrointestinal in nature. Syncope, defined as loss of consciousness and muscle tone, occurred in 12.6% of patients in the high-dose group. Conclusions: The observed improvements in ADAS-Cog and CIBIC+ following treatment with xanomeline provide the first evidence, from a large-scale, placebo-controlled clinical trial, that a direct-acting muscarinic receptor agonist can improve cognitive function in patients with AD. Furthermore, the dramatic and favorable effects on disturbing behaviors in AD suggest a novel approach for treatment of noncognitive symptoms.

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. Depression and Anxiety 6:31–39, 1997. © 1997 Wiley-Liss, Inc.

Olanzapine is a potential new "atypical" antipsychotic agent. This double-blind, acute phase study compared two doses of olanzapine [1 mg/day (Olz1.0); 10 mg/day (Olz10.0)] with placebo in the treatment of 152 patients who met the DSM-III-R criteria for schizophrenia and had a Brief Psychiatric Rating Scale (BPRS)-total score (items scored 0-6)or = 24. In overall symptomatology improvement [BPRS-total score and Positive and Negative Syndrome Scale (PANSS)-total score], Olz10.0 was statistically significantly superior to placebo. In positive symptom improvement (PANSS-positive score, BPRS-positive score), Olz10.0 was statistically significantly superior to placebo. In negative symptom improvement (PANSS-negative score), Olz10.0 was statistically superior to placebo. Olz 1.0 was clinically comparable to placebo in all efficacy comparisons. The only adverse event to show an overall statistically significant incidence difference was anorexia (reported for 10% of placebo-treated and 0% of Olz10.0-treated patients). The Olz10.0-treated patients improved over baseline with respect to parkinsonian and akathisia symptoms, and these changes were comparable with those observed with placebo. There were no dystonias associated with Olz10.0 treatment. At endpoint, the incidence of patients with elevated prolactin values did not differ statistically significantly between placebo-treated and Olz10.0-treated patients. Olanzapine appears to be not only safe and effective, but a promising atypical antipsychotic candidate.

Olanzapine is a potential new "atypical" antipsychotic agent. The double-blind acute phase of this study compared three dosage ranges of olanzapine (5 +/- 2.5 mg/day [Olz-L], 10 +/- 2.5 mg/day [Olz-M], 15 +/- 2.5 mg/day [Olz-H]) to a dosage range of haloperidol (15 +/- 5 mg/day [Hal]) and to placebo in the treatment of 335 patients who met the DSM-III-R criteria for schizophrenia. In overall symptomatology improvement (Brief Psychiatric Rating Scale [BPRS]-total), Olz-M, Olz-H, and Hal were significantly superior to placebo. In positive symptom improvement (BPRS-positive), Olz-M, Olz-H, and Hal were comparable and significantly superior to placebo. In negative symptom improvement (Scale for the Assessment of Negative Symptoms [SANS]-composite), Olz-L and Olz-H were significantly superior to placebo and Olz-H was also significantly superior to Hal. The most common treatment-emergent adverse events included somnolence, agitation, asthenia, and nervousness. No acute dystonia was observed with olanzapine. Treatment-emergent parkinsonism occurred with Olz-H at approximately one-third the rate of Hal, and akathisia occurred with Olz-H at approximately one-half the rate of Hal. Prolactin elevations associated with olanzapine were not significantly greater than those observed with placebo and were also significantly less than those seen with haloperidol.

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) of 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 (Δ) were similar for IMI (183 ± 329 fmol/mg) and FLU (196 ± 402 fmol/mg), a statistically significant treatment difference in ΔKD emerged (IMI -0.005 ± 0.010 pmol/ml versus FLU 0.08 ± 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.

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

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.

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 ≥ 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.

Depression in the geriatric population is a frequents, serious, and potentially reversible disorder, yet relatively few blinded, controlled, antidepressant trial 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.

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.

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)