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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.

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.

Background Neurocognitive deficits are severe in first-episode psychosis. Methods Patients (N = 263) with first-episode psychosis (schizophrenia, schizoaffective, or schizophreniform disorders) were randomly assigned to double-blind treatment with olanzapine (mean 11.30 mg/day) or haloperidol (mean 4.87 mg/day) for 104 weeks. A neurocognitive battery was administered at baseline (n = 246) and 12 (n = 167), 24 (n = 126), 52 (n = 89), and 104 (n = 46) weeks during treatment. Weighted principal component and unweighted composite scores were derived from individual tests. Results Both treatment groups demonstrated significant improvement on both composite scores. On the basis of the weighted composite score, olanzapine had greater improvement than haloperidol only at 12 (p = .014) and 24 (p = .029) weeks. For the unweighted composite, olanzapine had significantly better improvement compared with haloperidol only at week 12 (p = .044). At week 12 only, olanzapine improved performance on the Digit Symbol and Continuous Performance Test significantly more than haloperidol. Conclusions Both antipsychotic agents appeared to improve neurocognitive functioning among first-episode psychosis patients with schizophrenia. A significantly greater benefit in terms of neurocognitive improvement was found with olanzapine than with haloperidol at weeks 12 and 24.

Treatment effects are often evaluated by comparing change over time in outcome measures; however, valid analyses of longitudinal data can be problematic, particularly if some data are missing. For decades, the last observation carried forward (LOCF) approach has been a common method of handling missing data. Considerable advances in statistical methodology and our ability to implement those methods have been made in recent years. Thus, it is appropriate to reconsider analytic approaches for longitudinal data. This review examines the following from a clinical perspective: 1) the characteristics of missing data that influence analytic choices; 2) the attributes of common methods of handling missing data; and 3) the use of the data characteristics and the attributes of the various methods, along with empirical evidence, to develop a robust approach for the analysis and interpretation of data from longitudinal clinical trials. We propose that, in many settings, the primary efficacy analysis should use a repeated measures, likelihood-based, mixed-effects modeling approach, with LOCF used as a secondary, composite measure of efficacy, safety, and tolerability. We illustrate how repeated-measures analyses can be used to enhance decision-making, and we review the caveats that remain regarding the use of LOCF as a composite measure.

As part of the National Institute of Mental Health Strategic Plan for Mood Disorders Research effort, the Clinical Trials and Translation Workgroup was asked to define priorities for clinical trials in mood disorders and for research on how best to translate the results of such research to clinical practice settings. Through two face-to-face meetings and a series of conference calls, we established priorities based on the literature to date and what was known about research currently in progress in this area. We defined five areas of priority that cut across developmental stages, while noting that research on adult mood disorders was at a more advanced stage in each of these areas than research on child or geriatric disorders. The five areas of priority are: 1) maximizing the effectiveness and cost-effectiveness of initial (acute) treatments for mood disorders already known to be efficacious in selected populations and settings when they are applied across all populations and care settings; 2) learning what further treatments or services are most likely to reduce symptoms and improve functioning when the first treatment is delivered well, but the mood disorder does not remit or show adequate improvement; 3) learning what treatments or services are most cost-effective in preventing recurrence or relapse and maintaining optimal functioning after a patient's mood disorder has remitted or responded maximally to treatment; 4) developing and validating clinical, psychosocial, biological, or other markers that predict: a) which treatments are most effective, b) course of illness, c) risk of adverse events/tolerability and acceptability for individual patients or well-defined subgroups of patients; 5) developing clinical trial designs and methods that result in lower research costs and greater generalizability earlier in the treatment development and testing process. A rationale for the importance of each of these priorities is provided.

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.

Background: Depressive symptoms are a common feature of schizophrenia and may represent a core part of the illness. Where present, it has been associated with greater overall morbidity and mortality. Monotherapy with conventional dopamine antagonists may either worsen or bestow a limited therapeutic benefit. Accordingly the use of adjunctive thymoleptics has been explored. In contrast, olanzapine (OLZ), an atypical antipsychotic agent, offers a distinctive and pleotropic pharmacology suggestive of a broader efficacy profile than conventional neuroleptic agents. Methods: In a 6-week placebo- and haloperidol (HAL)-controlled trial with 335 randomized subjects with chronic schizophrenia in an acute exacerbation, three fixed dose ranges of OLZ (5, 10, or 15 ± 2.5 mg) were evaluated versus HAL (10–20 mg) or placebo. Results: Baseline to endpoint change in the Brief Psychiatric Rating Scale including the anxiety–depression cluster (items 1, 2, 5, 9) was analyzed. Two dose ranges of OLZ (10 ± 2.5, 15 ± 2.5) were superior to placebo (p Conclusions: Contributions from a more selective mesolimbic dopaminergic profile, D 1 or D 4 activity, the release of dopamine/norepinephrine in the prefrontal cortex, and/or serotonin 5-HT 2A,C antagonism may explain the differential benefit seen with OLZ in the treatment of comorbid anxious and depressive symptoms in schizophrenia.

The etiology of Alzheimer's dementia (AD) is unknown, but several neurotransmitters, e.g., acetylcholine, have been implicated. Recently, the group of calcium channel antagonists have been reviewed for their potential neuropsychiatric applications. These agents are capable of enhancing cholinergic tone, neurofilament/microtubular stabilization, and regional perfusion rates. The following is a report of a randomized, double-blind, placebo-controlled, multicenter study of 227 AD patients treated with nimodipine, a 1.4 dihydropyridine derivative and calcium channel antagonist. The subgroup receiving active drug (30 mg t.i.d.) experienced a prophylactic benefit across eight measures over 12 treatment weeks when contrasted with the disease progression seen among placebo recipients. Calcium channel blockers as neurotransmitter modulators and/or via calcium's theoretical role in neurofibrillary tangles, proteolysis, or neurofilament formation may represent a therapeutic opportunity for the AD patient.

Method:Patients (n = 243) with a diagnosisof panic disorderwere randomizedto treatmentwith fluoxetineor placebo.primary outcome measureswerechangein totalpanicattackfrequencyandCGI-improvement.Otherassessmentsincludedclinicianandpatient-ratedversionsof the panic and phobic disorder change scale, a phobia rating scale, HAMA,HAMD-21,andSheehanDisabilityscale.Correlationsbetween outcomesin individualsymptomdomainsand overallclinicaloutcome were determined,as were patternsof response.