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Treatment resistance constitutes the highest burden of disease within schizophrenia. We hypothesized that the synergistic activity of Lu AF35700 at dopamine Dsub1/suband Dsub2/subreceptors might provide superior antipsychotic effects versus first-line antipsychotic therapy in patients with treatment resistant schizophrenia (TRS), with a benign tolerability profile.This was a randomized, double-blind, active-controlled clinical trial (NCT02717195) followed by a one year open-label safety extension (NCT02892422). Following prospective confirmation of treatment resistance, patients were randomized (1:1:1) to 10 weeks double-blind treatment with Lu AF35700 10 mg or 20 mg, or active comparator (risperidone or olanzapine).1628 patients were screened for TRS, of which 1092 entered the prospective confirmation period. Of these, 697 were randomized (Lu AF35700 10 mg n = 235, 20 mg n = 232, comparator n = 230) and 395 discontinued before randomization, including 264 (24 %) who responded to treatment. 586 patients completed the double-blind phase, of which 524 entered the open-label extension and 318 completed 1-year of open-label treatment. At the end of the double-blind phase, the mean ± SE change in positive and negative syndrome scale (PANSS) total score was -10.1 ± 0.96 for Lu AF35700 10 mg, -8.22 ± 0.98 for Lu AF35700 20 mg, and - 9.90 ± 0.97 for the comparator group. Treatment differences [95 % CI] versus comparator treatment were non-significant (-0.12 [-2.37; 2.13] and 1.67 [-0.59; 3.94], respectively). The most common adverse events with Lu AF35700 were increased weight and headache. Prolactin values decreased by ≥50 % in both sexes treated with Lu AF35700.Despite evidence of antipsychotic efficacy, treatment with Lu AF35700 failed to differentiate from conventional antipsychotic treatment for patients with TRS.

Background: A proportion of people with treatment-resistant schizophrenia fail to show improvement on clozapine treatment. Knowledge of the sociodemographic and clinical factors predicting clozapine response may be useful in developing personalised approaches to treatment. Methods: This retrospective cohort study used data from the electronic health records of the South London and Maudsley (SLaM) hospital between 2007 and 2011. Using the Least Absolute Shrinkage and Selection Operator (LASSO) regression statistical learning approach, we examined 35 sociodemographic and clinical factors’ predictive ability of response to clozapine at 3 months of treatment. Response was assessed by the level of change in the severity of the symptoms using the Clinical Global Impression (CGI) scale. Results: We identified 242 service-users with a treatment-resistant psychotic disorder who had their first trial of clozapine and continued the treatment for at least 3 months. The LASSO regression identified three predictors of response to clozapine: higher severity of illness at baseline, female gender and having a comorbid mood disorder. These factors are estimated to explain 18% of the variance in clozapine response. The model’s optimism-corrected calibration slope was 1.37, suggesting that the model will underfit when applied to new data. Conclusions: These findings suggest that women, people with a comorbid mood disorder and those who are most ill at baseline respond better to clozapine. However, the accuracy of the internally validated and recalibrated model was low. Therefore, future research should indicate whether a prediction model developed by including routinely collected data, in combination with biological information, presents adequate predictive ability to be applied in clinical settings.

Background: There is evidence of heterogeneity within treatment-resistant schizophrenia (TRS), with some people not responding to antipsychotic treatment from illness onset and others becoming treatment-resistant after an initial response period. These groups may have different aetiologies. Aim: This study investigates sociodemographic and clinical correlates of early onset of TRS. Method: Employing a retrospective cohort design, we do a secondary analysis of data from a cohort of people with TRS attending the South London and Maudsley. Regression analyses were conducted to identify the correlates of the length of treatment to TRS. Predictors included the following: gender, age, ethnicity, problems with positive symptoms, problems with activities of daily living, psychiatric comorbidities, involuntary hospitalisation and treatment with long-acting injectable antipsychotics. Results: In a cohort of 164 people with TRS (60% were men), the median length of treatment to TRS was 3 years and 8 months. We observed no cut-off on the length of treatment until TRS presentation differentiating between early and late TRS (i.e. no bimodal distribution). Having mild to very severe problems with hallucinations and delusions at the treatment start was associated with earlier TRS (~19 months earlier). In sensitivity analyses, including only complete cases (subject to selection bias), treatment with a long-acting injectable antipsychotic was additionally associated with later TRS (~15 months later). Conclusion: Our findings do not support a clear separation between early and late TRS but rather a continuum of the length of treatment before TRS onset. Having mild to very severe problems with positive symptoms at treatment start predicts earlier onset of TRS.

The real-world impact of psychosis prevention is reliant on effective strategies for identifying individuals at risk. A transdiagnostic, individualized, clinically-based risk calculator to improve this has been developed and externally validated twice in two different UK healthcare trusts with convincing results. The prognostic performance of this risk calculator outside the UK is unknown. All individuals who accessed primary or secondary health care services belonging to the IBM® MarketScan® Commercial Database between January 2015 and December 2017, and received a first ICD-10 index diagnosis of nonorganic/nonpsychotic mental disorder, were included. According to the risk calculator, age, gender, ethnicity, age-by-gender, and ICD-10 cluster diagnosis at index date were used to predict development of any ICD-10 nonorganic psychotic disorder. Because patient-level ethnicity data were not available city-level ethnicity proportions were used as proxy. The study included 2,430,333 patients with a mean follow-up of 15.36 months and cumulative incidence of psychosis at two years of 1.43%. There were profound differences compared to the original development UK database in terms of case-mix, psychosis incidence, distribution of baseline predictors (ICD-10 cluster diagnoses), availability of patient-level ethnicity data, follow-up time and availability of specialized clinical services for at-risk individuals. Despite these important differences, the model retained accuracy significantly above chance (Harrell’s C = 0.676, 95% CI: 0.672–0.679). To date, this is the largest international external replication of an individualized prognostic model in the field of psychiatry. This risk calculator is transportable on an international scale to improve the automatic detection of individuals at risk of psychosis.

The reproducibility of machine-learning analyses in computational psychiatry is a growing concern. In a multimodal neuropsychiatric dataset of antipsychotic-naïve, first-episode schizophrenia patients, we discuss a workflow aimed at reducing bias and overfitting by invoking simulated data in the design process and analysis in two independent machine-learning approaches, one based on a single algorithm and the other incorporating an ensemble of algorithms. We aimed to (1) classify patients from controls to establish the framework, (2) predict short- and long-term treatment response, and (3) validate the methodological framework. We included 138 antipsychotic-naïve, first-episode schizophrenia patients with data on psychopathology, cognition, electrophysiology, and structural magnetic resonance imaging (MRI). Perinatal data and long-term outcome measures were obtained from Danish registers. Short-term treatment response was defined as change in Positive And Negative Syndrome Score (PANSS) after the initial antipsychotic treatment period. Baseline diagnostic classification algorithms also included data from 151 matched controls. Both approaches significantly classified patients from healthy controls with a balanced accuracy of 63.8% and 64.2%, respectively. Post-hoc analyses showed that the classification primarily was driven by the cognitive data. Neither approach predicted short- nor long-term treatment response. Validation of the framework showed that choice of algorithm and parameter settings in the real data was successfully guided by results from the simulated data. In conclusion, this novel approach holds promise as an important step to minimize bias and obtain reliable results with modest sample sizes when independent replication samples are not available.

Background: Many individuals who will experience a first episode of psychosis (FEP) are not detected before occurrence, limiting the effect of preventive interventions. The combination of machine-learning methods and electronic health records (EHRs) could help address this gap. Methods: This case-control development and validation study is based on EHR data from IBM Explorys. The IBM Explorys Platform holds standardised, longitudinal, de-identified, patient-level EHR data pooled from different health-care systems with distinct EHRs. The present EHR-based studies were retrospective, matched (1:1), case-control studies compliant with RECORD, STROBE, and TRIPOD statements. The study included individuals in the IBM Explorys database who at some point between 1990 and 2018 had a diagnosis of FEP followed by schizophrenia, and psychosis-free matched control individuals from a random subsample of the full cohort. For every individual in the FEP cohort, the individual in the control cohort was matched to have a similar date for inclusion in the database and a similar total observation time. Individuals in the FEP cohort had their index date defined as the first diagnosis of psychosis or the first prescription of antipsychotic medication. Individuals in the control cohort had their index date defined to occur the same number of days after inclusion in the database as their matching FEP individual. The FEP and control cohorts were both randomly split into development and validation datasets in a ratio of 7:3. The subset of individuals in the validation dataset who had all their health-care encounters at providers that were not seen in the development dataset made up the external validation subset. A novel recurrent neural network model was developed to predict the risk of FEP 1 year before the index date by employing demographics and medical events (in the categories diagnoses, prescriptions, procedures, encounters and admissions, observations, and laboratory test results) dynamically collected in the EHR as part of clinical routine. We named the recurrent neural network Dynamic ElecTronic hEalth reCord deTection (DETECT). The main outcomes were accuracy and area under receiver operating characteristic curve (AUROC). Decision-curve analyses and dynamic patient journey plots were used to evaluate clinical usefulness. Findings: The FEP and control cohorts each comprised 72 860 individuals. 102 030 individuals (51 015 matching pairs) were randomly allocated to the development dataset and the remaining 43 690 to the validation dataset. In the validation dataset, 4770 individuals had all their encounters outside of the 118 790 health-care providers that were encountered in the development dataset. The data from these individuals made up the external validation subset. The median follow-up (observation time before index date) was 6·0 years (IQR 3·0–10·4). In the development dataset, DETECT's prognostic accuracy was 0·787 and AUROC was 0·868. In the validation dataset, DETECT's prognostic accuracy was 0·774 and AUROC was 0·856. In the external test subset, DETECT's balanced prognostic accuracy was 0·724 and AUROC was 0·799. Prevalence-adjusted decision-curve analyses suggested that DETECT was associated with a positive net benefit in two different scenarios for FEP detection. Interpretation: DETECT showed adequate prognostic accuracy to detect individuals at risk of developing a FEP in primary and secondary care. Replication and refinement in a population-based setting are needed to consolidate these findings. Funding: Lundbeck.

Background The treatment response of patients with schizophrenia is heterogeneous, and markers of clinical response are missing. Studies using machine learning approaches have provided encouraging results regarding prediction of outcomes, but replicability has been challenging. In the present study, we present a novel methodological framework for applying machine learning to clinical data. Herein, algorithm selection and other methodological choices were based on model performance on a simulated dataset, to minimize bias and avoid overfitting. We subsequently applied the best performing machine learning algorithm to a rich, multimodal neuropsychiatric dataset. We aimed to 1) classify patients from controls, 2) predict short- and long-term clinical response in a sample of initially antipsychotic-naïve first-episode schizophrenia patients, and 3) validate our methodological framework. Methods We included data from 138 antipsychotic-naïve, first-episode schizophrenia patients, who had undergone assessments of psychopathology, cognition, electrophysiology, structural magnetic resonance imaging (MRI). Perinatal data and long-term outcome measures were obtained from Danish registers. Baseline diagnostic classification algorithms also included data from 151 matched healthy controls. Short-term treatment response was defined as change in psychopathology after the initial antipsychotic treatment period. Long-term treatment response (4–16 years) was based on data from Danish registers. The simulated dataset was generated to resemble the real data with respect to dimensionality, multimodality, and pattern of missing data. Noise levels were tunable to enable approximation to the signal-to-noise ratio in the real data. Robustness of the results was ensured by running two parallel, fundamentally different machine learning pipelines, a ‘single algorithm approach’ and an ‘ensemble approach’. Both pipelines included nested cross-validation, missing data imputation, and late integration. Results We significantly classified patients from controls with a balanced accuracy of 64.2% (95% CI = [51.7, 76.7]) for the single algorithm approach and 63.1% (95% CI = [50.4, 75.8]) for the ensemble approach. Post hoc analyses showed that the classification primarily was driven by the cognitive data. Neither approach predicted short- and long-term clinical response. To validate our methodological framework based on simulated data, we selected the best, a medium, and the most poorly performing algorithm on the simulated data and applied them to the real data. We found that the ranking of the algorithms was kept in the real data. Discussion Our rigorous modelling framework incorporating simulated data and parallel pipelines discriminated patients from controls, but our extensive, multimodal neuropsychiatric data from antipsychotic-naïve schizophrenia patients were not predictive of the clinical outcome. Nevertheless, our novel approach holds promise as an important step to obtain reliable, unbiased results with modest sample sizes when independent replication samples are not available.

Developing new innovative and effective medications for such broad disease indications as schizophrenia and major depression is challenged by the great heterogeneity in pathophysiology and phenotype inherent in these clinical diagnoses. Targeting development efforts to a subset of those patients who may share a homogeneous set of disease-mediating features may offer a more effective pathway for bringing drugs to market. Disease prognostic and treatment predictive biomarkers may be used to identify subpopulations of patients that are more likely to respond to a specific treatment. Enrichment of clinical trials with such tailored populations may enhance signal detection through testing potential drugs that target a disease substrate common to the patient cohort under investigation. Such an approach has the potential to improve the efficiency and success rate of the clinical trials for CNS drug development. Several examples from recent clinical trial investigations in schizophrenia and major depression illustrate the potential benefit of such an enrichment strategy. With increasing discovery and identification efforts for relevant prognostic and predictive biomarkers in schizophrenia and depression, an increased probability of successful drug development to meet unsatisfied therapeutic needs across major psychiatric disorders may be achieved.

International Society for CNS Clinical Trials and Methodology convened an expert Working Group that assembled consistency/inconsistency flags for the Montgomery-Asberg Depression Rating Scale (MADRS). Twenty-two flags were identified. Seven flags are believed to be strong flags that suggest that a thorough review of rating is warranted. The flags were applied to assessments derived from the NEWMEDS data repository. Almost 65% of ratings had at least one inconsistency flag raised and 22% had two or more. Application of flags to clinical ratings may improve reliability of ratings and validity of trials.

Aberrant glutamate neurotransmission, and in particular dysfunction of the N-methyl-D-aspartate receptor (NMDAR), has been implicated in psychiatric disorders and represents a novel therapeutic target. Low-dose administration of the NMDA antagonist ketamine in healthy volunteers elicits a strong blood oxygenation level dependent (BOLD) imaging signal that can be attenuated by pretreatment with single, therapeutically effective doses of marketed medicines interacting with the glutamate system.To test the attenuation of the ketamine-induced BOLD signal by pretreatment with either a metabotropic glutamate receptor (mGluR) 2/3 or a mGluR2 agonist in healthy volunteers METHODS: We used a ketamine challenge pharmacological magnetic resonance imaging (phMRI) paradigm to assess the modulatory effects of single acute doses of LY2140023 (pomaglumetad methionil), the methionine prodrug of the mGluR2/3 agonist LY404039 (10, 40, and 160 mg; N = 16 subjects) and of LY2979165, and the alanine prodrug of the selective orthosteric mGluR2 agonist 2812223 (20 and 60 mg; N = 16 subjects).A reduction in the ketamine-evoked BOLD phMRI signal relative to placebo was observed at the highest doses tested of both LY2140023 and LY2979165. A relationship was observed between reduction of the BOLD signal and increasing plasma levels of 2812223 in the LY2979165 cohort.These results identify pharmacologically active doses of the group II mGluR agonist prodrugs LY2140023 and LY2979165 in humans. They also extend the classes of compounds that have been experimentally shown to reverse the ketamine-evoked phMRI signal in humans, further supporting the use of this method as a neuroimaging biomarker for assessing functional effects.

This 6-week, multicenter, randomized withdrawal, placebo-controlled trial sought to determine whether symptoms of physical dependence occur after abrupt cessation of pomaglumetad methionil (LY2140023 monohydrate), a metabotropic glutamate 2/3 receptor agonist, in patients with schizophrenia. Eligible outpatients, 18 to 65 years old who required a modification or initiation of antipsychotic medication received 4 weeks of pomaglumetad methionil during open-label treatment and then were randomized, double-blind, to continue pomaglumetad methionil or receive placebo for 2 weeks. The primary outcome compared results of the 3-day moving mean of the total score on the Discontinuation Symptom Checklist-Modified Rickels for pomaglumetad methionil-treated patients with those on placebo during the randomized withdrawal phase. An electronic patient-reported outcome (ePRO) device was used daily to record these results. During the withdrawal phase, 103 patients were randomized, and 98 patients completed the trial. There was no statistically significant evidence of withdrawal symptoms associated with placebo compared with pomaglumetad methionil continuation as measured by Discontinuation Symptom Checklist-Modified Rickels (P = 0.170). The results are supported by secondary analyses with the clinician-rated, Clinical Institute Withdrawal Assessment of Alcohol Scale Revised, which showed no statistically significant differences between treatment groups. Using the ePRO device, 82.5% of the patients achieved 75% to 100% of compliance. No discontinuations due to worsening of schizophrenia, serious adverse events, deaths, or seizures were reported during either phase of the study. These findings suggest that there is no evidence of withdrawal symptoms associated with the abrupt discontinuation of pomaglumetad methionil and that an ePRO device can be successfully used in a multicenter schizophrenia trial.

Outcomes in RCT's of antipsychotic medications are often examined using last observation carried forward (LOCF) and mixed effect models (MMRM), these ignore meaning of non-completion and thus rely on questionable assumptions. We tested an approach that combines into a single statistic, the drug effect in those who complete trial and proportion of patients in each treatment group who complete trial. This approach offers a conceptually and clinically meaningful endpoint. Composite approach was compared to LOCF (ANCOVA) and MMRM in 59 industry sponsored RCT's. For within study comparisons we computed effect size (z-score) and p values for (a) rates of completion, (b) symptom change for complete cases, which were combined into composite statistic, and (c) symptom change for all cases using last observation forward (LOCF). In the 30 active comparator studies, composite approach detected larger differences in effect size than LOCF (ES=.05) and MMRM (ES=.076). In 10 of the 49 comparisons composite lead to significant differences (p≤.05) where LOCF and MMRM did not. In 3 comparisons LOCF was significant, in 2 MMRM lead to significant differences whereas composite did not. In placebo controlled trials, there was no meaningful difference in effect size between composite and LOCF and MMRM when comparing placebo to active treatment, however composite detected greater differences than other approaches when comparing between active treatments. Composite was more sensitive to effects of experimental treatment vs. active controls (but not placebo) than LOCF and MMRM thereby increasing study power while answering a more relevant question.

Background Negative symptoms are an important target for intervention in schizophrenia. There is lack of clarity in defining appropriate patients for negative symptom trials. While regulators, drug developers and academics have expressed positions in this regard, the implications of these definitions are not yet tested in large-scale trials and there is no consensus. Objectives We examined the extent to which various operational criteria for inclusion in negative symptoms in schizophrenia clinical trials can impact patient selection and examined the effectiveness of second generation antipsychotics (SGAs) in patients with various degrees of negative symptoms. Method Using anonymized patient data from AstraZeneca, Janssen Pharmaceuticals, Eli Lilly, Lundbeck, and Pfizer from 20 placebo-controlled trials of SGAs in schizophrenia from the NewMeds repository, we applied different criteria for negative symptoms: prominent, predominant, and EMA criteria, which require predominant and core negative symptoms to be present and examined the impact of these on inclusion and outcome. Results Operational criteria for negative symptoms in trials vary greatly in their inclusion of patients from “typical” trial samples. Of the patients in our studies, 8.1% and 62.3% met criteria for prominent negative symptoms, 10.2% to 50.2% met criteria for predominant negative symptoms and 7.6% to 40.0% met EMA criteria at baseline. After 6 weeks of active treatment, 8% and 33.1% of patients met criteria for prominent residual negative symptoms and 14.9% to 65% met criteria for prominent and 12.2% to 45.5% met EMA criteria. Patients with predominant or prominent negative symptoms showed marked improvement on second generation antipsychotics. Conclusions Applying various operational criteria for selecting patients for negative symptoms trials provides a great variability in percentage of suitable patients calling into question the extent to which some definitions may be overly narrow.

Backgroud: Elevated prolactin (hyperprolactinemia) has been commonly reported during treatment with some an-tipsychotic drugs. A decrease in bone mineral density (BMD) may be related to elevated prolactin. The objective of this study was to determine the prevalence of low BMD in patients with schizophrenia treated with conventional antipsychotics or risperidone and to evaluate any potential relationship with treatment. Methods: A large-scale, cross-sectional secondary analysis was performed to determine low BMD in schizophrenia patients (n=402) treated with conventional antipsychotics or risperidone for at least three months prior to study entry. BMD was determined by ultrasonography of the calcaneus. The potential effect of age, elevated prolactin, and duration of antipsychotic drug treatment on BMD was evaluated. Bone metabolism measures were determined and the potential effect of elevated prolactin and sex hormones on bone metabolism measures was also evaluated. Regression analysis was used for all the...

Background Endogenous opioid-mediated reward pathways may play a role in the development and maintenance of alcohol dependence. This study tested whether LY2196044, an opioid receptor antagonist, in combination with medical management would reduce drinking in alcohol-dependent patients. Methods This was a multicenter, outpatient, randomized, double-blind, parallel, and placebo-controlled trial with a 16-week treatment period. Patients (N = 375) were alcohol-dependent, treatment-seeking adults. Patients were randomly assigned to once-daily LY2196044 (final doses of 125 or 250 mg/d) or placebo. DNA samples were collected at baseline. At each visit, patients underwent safety assessments, laboratory testing, efficacy measures, and medical management. Blood samples were also obtained for pharmacokinetic testing. The primary measure was the change from baseline in the percent heavy drinking days (HDD). Secondary efficacy measures were percent days abstinent per month and number of drinks per day. Results The treatment difference in change from baseline in % HDD between LY2196044 and placebo was not statistically significant (−43.02 vs. −38.72%, respectively; p = 0.12). There was a trend toward greater change from baseline in the percent days abstinent per month for the LY2196044 group compared with the placebo group (33.49 vs. 28.12%, respectively; p = 0.051). The decrease from baseline for mean number of drinks per day was statistically significantly greater in the LY2196044 group compared with the placebo group (−5.37 vs. −4.66 drinks per day, respectively; p = 0.013). LY2196044-treated patients who were dopamine receptor type 4–variable number tandem repeat L carriers had greater reductions in % HDD (p = 0.0565), increased percent days abstinent (p = 0.0496), and reduced drinks per day (p = 0.0069) than placebo-treated L carriers. The safety profile for LY2196044 appeared similar to that of other opioid antagonists. Conclusions The results from this proof-of-concept clinical trial warrant further evaluation of LY2196044 for the treatment of alcohol dependence.

Pomaglumetad methionil (LY2140023 monohydrate, hereafter referred to as LY2140023) is currently in clinical development as a potential new treatment for schizophrenia. If found to be effective, LY2140023 would represent a novel non-dopaminergic based therapy for this disorder that may restore balance to the glutamate dysregulation hypothesized to underlie schizophrenia. This article presents available clinical trial data that describe the safety, tolerability, and efficacy of LY2140023 in patients with schizophrenia. Data indicate that this compound appears to have an efficacy profile consistent with currently available antipsychotic drugs, although confirmation of its efficacy awaits further clinical testing. LY2140023 is generally well tolerated and appears to have a low association with adverse events related to dopamine D2 receptor antagonism and with weight gain, which are commonly seen with current antipsychotics. A potential association of LY2140023 treatment and seizure events has been identified, although an accurate and reliable understanding of the incidence of these events requires further clinical testing, which is underway. Evaluation of the safety, tolerability, and efficacy of LY2140023 is continuing. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

International Society for CNS Clinical Trials and Methodology convened an expert working-group that assembled consistency/inconsistency flags for the Positive and Negative Syndrome Scale (PANSS). Twenty-four flags were identified and divided based on extent to which they represent error (Possibly, Probably, Very probably or definitely). The flags were applied to assessments derived from the NEWMEDS data repository and the CATIE clinical trial data. Almost 40% of ratings had at least one inconsistency flag raised and 10% had two. Application of flags to clinical rating can improve reliability and validity of trials.

The aim of this study was to determine what variables predict a 'combined treatment outcome' (COMBOUT) in patients with chronic schizophrenia.This analysis (n=522) was based on a randomized, double-blind, flexible-dose, 12-week study that enrolled chronically-ill patients diagnosed with schizophrenia or a related disorder. COMBOUT was assessed using the PANSS for symptoms, CGI-S for overall clinical status, MADRS for depressive symptoms, QLS for functioning/QOL, and SWN-K for subjective well-being. Possible predictors included demographics as well as baseline scores (Model I), and early change (week 2) scores (Model II).Model I: significantly better outcome (higher COMBOUT score) was observed in patients with lower MADRS (T= - 6.36; p0.001) or higher QLS (T=5.05; p0.001) scores at baseline. Model II: significantly better COMBOUT was observed in patients with early improvement of QLS (T=4.93; p0.001), SWN-K (T=3.88; p0.001), PANSS (T= - 2.32; p=0.021) and CGI-S scores (T= - 2.22; p=0.027). Changes in EPS were not predictors of COMBOUT in the models tested.COMBOUT at endpoint was predicted by lower depressive symptom score and higher QOL at baseline and by early improvement in psychopathology, quality of life and subjective well-being.

Louis S Matza,1 Glenn A Phillips,2 Dennis A Revicki,1 Haya Ascher-Svanum,3 Karen G Malley,4 Andrew C Palsgrove,1 Douglas E Faries,3 Virginia Stauffer,3 Bruce J Kinon,3 A George Awad,5 Richard SE Keefe,6 Dieter Naber71Outcomes Research, United BioSource Corporation, Bethesda, MD, 2Formerly with Eli Lilly and Company, Indianapolis, IN, 3Eli Lilly and Company, Indianapolis, IN, 4Malley Research Programming, Inc, Rockville, MD, USA; 5Department of Psychiatry and Behavioral Sciences; University of Toronto, Toronto, Canada; 6Duke University Medical Center, Durham NC, USA; 7Universitaetsklinikum Hamburg-Eppendorf, Hamburg, GermanyIntroduction: The Reasons for Antipsychotic Discontinuation Interview (RAD-I) was developed to assess patients’ perceptions of reasons for discontinuing or continuing an antipsychotic. The current study examined reliability and validity of domain scores representing three factors contributing to these treatment decisions: treatment benefits, adverse events, and distal reasons other than direct effects of the medication.Methods: Data were collected from patients with schizophrenia or schizoaffective disorder and their treating clinicians. For approximately 25% of patients, a second rater completed the RAD-I for assessment of inter-rater reliability.Results: All patients (n = 121; 81 discontinuation, 40 continuation) reported at least one reason for discontinuation or continuation (mean = 2.8 reasons for discontinuation; 3.4 for continuation). Inter-rater reliability was supported (kappas = 0.63–1.0). Validity of the discontinuation domain scores was supported by associations with symptom measures (the Positive and Negative Syndrome Scale for Schizophrenia, the Clinical Global Impression – Schizophrenia Scale; r = 0.30 to 0.51; all P < 0.01), patients’ primary reasons for discontinuation, and adverse events. However, the continuation domain scores were not significantly associated with these other indicators.Discussion: Results support the reliability, convergent validity, and known-groups validity of the RAD-I for assessing patients’ reasons for antipsychotic discontinuation. Further research is needed to examine validity of the RAD-I continuation section.Keywords: discontinuation, antipsychotic, schizophrenia, treatment continuation, patient-reported outcomes, instrument development

The origin of modern psychopharmacology can be traced to the discovery of the first clinically efficacious antipsychotic drug, chlorpromazine, in 1952. Following this watershed advance, several additional antipsychotic agents of the same (i.e., phenothiazine) class, as well as others derived from the butyrophenone scaffold (e.g., haloperidol, 1958), were discovered and widely utilized in the treatment of schizophrenia patients. Arvid Carlsson and his colleagues were the first to show that antipsychotics of both the phenothiazine and butyrophenone classes acted via blockade of dopamine (DA) receptors [1]. This hypothesis was further refined over a decade later by observations that all antipsychotic drugs potently block dopamine D2-like receptors [2, 3]. Interest in moving to mechanisms of antipsychotic action other than dopamine D2

Ten phase 1 studies of LY2140023 monohydrate (LY2140023), an mGlu2/3 receptor agonist, in healthy male and female subjects were pooled to evaluate the adverse event profile. These studies included both single-dose (5-200 mg) and multiple-dose (20-160 mg 2 times a day) treatment groups. The percentage of subjects reporting treatment-emergent adverse events (TEAEs) were assessed in placebo and LY2140023 dose groups: 5 to 20, 40, 60 to 80, and more than 80 mg (120-200 mg). The severity and duration of TEAEs were also determined. Electroencephalograms were performed in 1 study to detect if there were any prodromal signs of convulsions or seizures. Subjects who received either placebo or LY2140023 and participated in the single-dose (n = 159) and multiple-dose (n = 102) treatment groups were included in these analyses. No clear trends for increased TEAE incidence occurred with higher doses of LY2140023 in both the single-dose and multiple-dose treatment groups. The TEAEs with the highest incidence were gastrointestinal and nervous system events. No serious adverse events occurred in any of the 10 studies, and most TEAEs were mild in severity and transient in nature. There were no clinically significant changes in electroencephalograms in subjects receiving LY2140023 (n = 26). LY2140023 was generally well tolerated in healthy subjects.

Patients with schizophrenia who have predominant negative symptoms are often considered less responsive to treatment. This analysis of patients with schizophrenia or schizoaffective disorder compares changes in symptom severity between those with predominant versus merely prominent negative symptoms. Prominent negative symptoms were defined by a baseline score of ≥4 on at least 3, or ≥5 on at least 2, of the 7 Positive and Negative Syndrome Scale (PANSS) negative subscale items. Predominant negative symptoms were defined by the foregoing plus a PANSS positive score of

Research has identified distinct trajectories of antipsychotic response in patients with chronic schizophrenia in short-duration trials (~12 weeks). This post-hoc analysis identified trajectories in patients with chronic schizophrenia treated for ≤24 weeks. We pooled data from 1990 patients with chronic schizophrenia from 6 randomized, double-blind, olanzapine-comparator trials of atypical antipsychotics. Trajectory analysis identified homogeneous subpopulations within the larger heterogeneous population. Baseline demographics were compared between the identified latent classes. Five distinct response trajectories based on Positive and Negative Syndrome Scale (PANSS) Total score were identified: Dramatic Responders (n=47/1990, 2.4%), severely-ill patients (PANSS=124) with rapid and sustained improvement (51%) by Week 3; Partial Responders (n=1802/1990, 90.6%), moderately-ill (PANSS=90) with minimal improvement (21%) by Week 4, and little further improvement; Partial Responders-Unsustained (Late) (n=32/1990, 1.6%), markedly-ill (PANSS=95) with minimal initial improvement followed by worsening after Week 12; Partial Responders-Unsustained (Early) (n=28/1990, 1.4%), markedly-ill (PANSS=102) with minimal initial improvement followed by worsening after Week 8; and Delayed Responders (n=81/1990, 4.1%), markedly-to-severely-ill (PANSS=113) with minimal (11%) improvement at Week 8, but noticeable improvement thereafter (49%). Significant differences were noted for several baseline characteristics (p

Early response to antipsychotic medication has been shown to accurately predict later response to continued use of the same treatment in patients with chronic schizophrenia. This study examines whether this predictive pattern exists for patients with first-episode psychosis. We used a data-driven threshold for early response of ≥ 26.2% improvement from baseline on the Positive and Negative Syndrome Scale (PANSS(0-6)) Total score to determine whether response at Week 2 of treatment may predict response at Week 12 in a randomized, double-blind trial of olanzapine versus haloperidol for treatment of patients with first-episode psychosis (N=225). Later response was defined as a ≥ 40% and ≥ 50% improvement in PANSS Total(0-6) score and as remission. At Week 2, 43% (97/225) of patients were identified as early responders. At a threshold for later response of ≥ 50% improvement in PANSS(0-6) Total score, early non-response most strongly predicted later non-response, demonstrating high specificity (74%) and high negative predictive value (80%). As had been seen in the treatment of patients with chronic schizophrenia, early non-response was a robust predictor of subsequent non-response in the treatment of patients with first-episode psychosis.

The goal of this study was to identify genetic markers associated with LY2140023 monohydrate response in patients with schizophrenia. Variants in eight candidate genes related to the mechanism of action of LY2140023 or olanzapine were investigated in a genetic cohort collected from two clinical trials. Results from this genetic analysis indicate that 23 single nucleotide polymorphisms (SNPs) were associated with a change in Positive and Negative Syndrome Scale total score in response to LY2140023 at 28 days (P

Extended placebo-controlled clinical trials in schizophrenia research pose an ethical challenge. This study examines factors that have implications for the design and duration of placebo-controlled acute efficacy trials: Does early response discriminate active drug (AD) from placebo, and are the early differences sustained over time? A post hoc pooled analysis of 2 randomized 6-week double-blind clinical trials was performed comparing patients with schizophrenia treated with placebo or low-dose olanzapine (1 mg/d; placebo/low dose [PBO] group, n = 170) to patients treated with a 10- to 20-mg/d dose of haloperidol or medium- to high-dose olanzapine (7.5 to 17.5 mg/d; AD group, n = 252). Mixed-model repeated-measure analysis tested for group differences. Power analysis was undertaken to compare study designs with shorter durations. At 2 weeks, the mean reduction in the Brief Psychiatric Rating Scale total score was significantly greater for the AD group (-10.1) compared with the PBO group (-4.1; P < 0.001); this difference was sustained until the study ended (6 weeks). A higher proportion of early treatment responders were observed for the AD group (52%) compared with the PBO group (29%; P < 0.001). Early nonresponse to placebo or drug was predictive of subsequent nonresponse (negative predictive value: PBO = 95%, AD = 84%). Power analysis indicates that the placebo-drug differences are robust at 2 weeks. Treatment responders from the AD and the PBO groups followed a similar response path. Early response to antipsychotic treatment discriminated AD from placebo. Reducing placebo-controlled clinical trials from 6 weeks to 2 to 4 weeks was found to be a viable option for efficacy identification in acutely ill patients.

Our objective was to prospectively assess whether early (ie, 2 weeks) response to an antipsychotic predicts later (12-week) response and whether 'switching' early non-responders to another antipsychotic is a better strategy than 'staying'. This randomized, double-blind, flexible-dosed, 12-week study enrolled 628 patients diagnosed with schizophrenia or schizoaffective disorder. All initiated treatment with risperidone. Early response was defined as > or =20% improvement on the Positive and Negative Syndrome Scale (PANSS) total score following 2 weeks of treatment. Early responders (ERs) continued on risperidone, whereas early non-responders (ENRs) were randomized (1 : 1) to continue on risperidone 2-6 mg/day or switch to olanzapine 10-20 mg/day for 10 additional weeks. Compared with ENRs, risperidone ERs showed significantly greater reduction in PANSS total score (end point; p

Clinical trial data were evaluated for the association between 22 single-nucleotide polymorphisms (SNPs) and response in acutely ill patients diagnosed with schizophrenia, schizoaffective disorder or schizophreniform disorder, who were treated with oral risperidone. All patients in the exploratory (78 African Americans) and validation (65 whites) data sets received risperidone 2-6 mg per day over 2-12 weeks. Two SNPs were found to have significant associations with response to risperidone over 2-12 weeks in both African-American and white patients and had a consistent direction of effect in both cohorts. Metabotropic glutamate receptor (GRM3) SNP, rs724226, was associated with a change in the positive and negative syndrome scale (PANSS) total response. Catechol-O-methyltransferase (COMT) SNP, rs165599, was moderately associated with a change in the PANSS Negative score. The greater prevalence of poor-responder GRM3 and COMT alleles in white versus African-American patients might have a clinical significance in evaluating the ethnic-specific response to risperidone.

Hong Liu-Seifert1, Bruce J Kinon1, Christopher J Tennant2, Jennifer Sniadecki1, Jan Volavka31Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA; 2CJT Biomedical Consulting, South Lake Tahoe, CA, USA; 3New York University, New York, NY, USAObjective: To better understand sexual dysfunction in patients with schizophrenia and its associations with prolactin and reproductive hormones.Methods: This was a secondary analysis of an open-label, one-day study (N = 402). The primary objective of the study was to assess the prevalence of hyperprolactinemia in patients with schizophrenia who had been treated with conventional antipsychotics or risperidone. Other atypical antipsychotics available at the time of the study were not included due to a more favorable prolactin profile.Results: The majority of patients (59% of females and 60% of males) reported impairment of sexual function. In postmenopausal females, risk of impaired sexual interest was increased by 31% for every 10 ng/ml increase in prolactin (p = 0.035). In males, lower testosterone was associated with higher prolactin (p

Treatment discontinuation is common in antipsychotic trials for the treatment of schizophrenia and is often associated with symptom worsening. This study assessed the timing and the magnitude of symptom change associated with treatment discontinuation for any cause, and whether improvement in specific symptom domains was predictive of treatment persistence. This post hoc analysis used pooled data from 1627 patients with schizophrenia spectrum disorders who were enrolled in 4 randomized, double-blind antipsychotic comparator trials of 24 to 28 weeks duration. Mean change in the Positive and Negative Syndrome Scale (PANSS) total scores during the last available visit interval were compared for patients who did and did not complete the trial. Improvements in positive, negative, and depression subscores of the PANSS were used to predict trial persistence. A total of 866 patients (53%) discontinued treatment of any cause during the studies. Patients who discontinued treatment early (weeks 0-4) had no significant improvement in mean PANSS total score during the last visit interval, whereas those who discontinued beyond week 4 had significant worsening of mean PANSS total score in the final visit interval. Improvements in either PANSS positive or depression subscores, but not in the PANSS negative subscore, were strongly predictive of study completion. These findings suggest that early failure to establish treatment response and later symptom worsening are associated with treatment discontinuation for any cause. Early improvement in positive or depressive/anxiety symptoms is especially predictive of treatment persistence.

Objective: To compare olanzapine, risperidone and typical antipsychotics on medication discontinuation for any cause during one-year, open-label treatment for schizophrenia. Methods: This post hoc analysis used data from a one-year, randomized, open-label, multi-site, cost-effectiveness study of schizophrenia conducted between May 1998 and September 2002. If clinically warranted, patients could switch antipsychotics. Patients randomized to olanzapine (n=222), risperidone (n=217) or typical antipsychotic of physician's choice (n=209) were compared on average time to all-cause medication discontinuation and survival rates over the one-year study. Results: The average time to all-cause discontinuation was longer for olanzapine than for risperidone (p

Objective: Early nonresponse to antipsychotics appears to predict subsequent nonresponse to treatment when assessed in randomized controlled trials of predominately acute inpatients treated for schizophrenia. This study assessed the predictive accuracy of early nonresponse to treatment and its clinical, functional, and economic ramifications in the naturalistic treatment of predominately chronic outpatients treated for schizophrenia. Methods: This post hoc analysis used data from a 1-year, randomized, open-label study of olanzapine, risperidone, and typical antipsychotics in the treatment of schizophrenia. If clinically warranted, patients could switch antipsychotics following 8 weeks of treatment. Patients completing 8 weeks of treatment (n = 443 of 664 enrollees) were included. Patients with early response (≥20% improvement from baseline on the Positive and Negative Syndrome Scale at 2 weeks) were compared with early nonresponders on symptom remission, functionality, perceptions of medication influence, and total health care costs at 8 weeks. Results: Early response/nonresponse at 2 weeks predicted subsequent response/nonresponse at 8 weeks with a high level of accuracy (72%) and specificity (89%). After 8 weeks, early nonresponders were less likely to achieve symptom remission (P < .001), improved less on functional domains (P < .05), perceived medication as less beneficial (P = .004), and incurred total heath care costs over twice that of early responders ($4349 vs $2102, P = .010). Conclusions: In the usual care of schizophrenia patients, early nonresponse appears to reliably predict subsequent nonresponse to continued treatment with the same medication to be associated with poorer outcomes and higher health care costs. Identifying early nonresponders may minimize prolonging exposure to suboptimal or ineffective treatment strategies.

Objective To test whether early onset of response to antipsychotic medications accurately predicts subsequent response in the treatment of patients with schizophrenia. Methods We used data from 5 randomized, double-blind clinical trials comparing olanzapine with other atypical antipsychotic drugs in the treatment of patients with schizophrenia and related disorders, who were at least moderately ill at baseline and who were treated for a minimum of 2 weeks (N = 1077). Early response was defined as ≥ 20% improvement on the PANSS total score at 2 weeks. Conditional probabilities (sensitivity, specificity, positive and negative predictive values) were used to characterize the likelihood of “subsequent response” to treatment (i.e., ≥ 40% improvement on the PANSS total score with treatment up to 3 months). Subsequent analyses focused on varying thresholds of subsequent response, and at different time points. Results Most (80%) of subsequent non-responders by 3 months were correctly classified as early non-responders at 2 weeks (high specificity), and 84% of early non-responders at 2 weeks were subsequent non-responders by 3 months (high negative predictive value). For early responders, prediction of subsequent response was substantially lower. A higher threshold (e.g., ≥ 40% improvement) had greater predictive accuracy at all time points measured. Early non-responders attained less symptom improvement overall, and were more likely to discontinue from treatment. Conclusions Early non-response to antipsychotic medications was a robust predictor of subsequent lack of response in the treatment of patients with schizophrenia. Evaluating patients as early as 2 weeks in treatment can help identify non-responders who may benefit from an alternative therapeutic approach.

Objectives: Substance abuse and schizophrenia comorbidity are common, and substance abuse may negatively affect schizophrenia treatment effectiveness. This research was conducted to determine whether lifetime history of substance abuse diagnosis or concurrent substance use is associated with poor prognosis in schizophrenia as measured by the treatment outcome in controlled clinical trials of atypical antipsychotics. Methods: A post hoc analysis of four randomized, double-blind, 24-to 28-week studies of schizophrenia treatment was performed to examine effect of historical substance abuse diagnosis on treatment outcome. Patients with a diagnosis of substance dependence within 1 or 3 months (specific to study) were excluded from the trials. Positive and Negative Syndrome Scale (PANSS) scores were compared between patients who had and did not have a history of substance abuse. PANSS scores were also compared between patients who reported different degrees of concurrent substance use for two of the tr...

To prospectively measure the link between depressive symptoms and functional outcomes in the long-term treatment of people with schizophrenia.Data were drawn from a large, multi-site, 3-year, prospective, naturalistic, observational study, in which subjects with schizophrenia were assessed at enrollment and at 12-month intervals thereafter. Individuals who were "Depressed" (defined as a total scoreor =16 on the Montgomery-Asberg Depression Rating Scale) at enrollment were compared to those "Non-depressed" on functional outcomes, using self-report measures, clinicians' ratings, and information from medical records. Statistical analyses included Generalized Estimation Equation and mixed regression analyses adjusted for individual characteristics. Longitudinal group comparisons across the 3-year study were augmented with a cross-sectional group comparison at enrollment.At enrollment, 39.4% (877/2228) of the participants were deemed Depressed. Across the 3-year study, the depressed cohort was significantly more likely than the Non-depressed to use relapse-related mental health services (emergency psychiatric services, sessions with psychiatrists); to be a safety concern (violent, arrested, victimized, suicidal); to have greater substance-related problems; and to report poorer life satisfaction, quality of life, mental functioning, family relationships, and medication adherence. Furthermore, changes in depressed status were associated with changes in functional outcomes.People with schizophrenia and concurrent depressive symptoms have poorer long-term functional outcomes compared to the Non-depressed. Their poorer quality of life, greater use of mental health services, and higher risk of involvement with law enforcement agencies underscore a need for special treatment interventions. Treatment of the non-psychotic dimensions of schizophrenia is a critical part of recovery.

Objective To determine the effect of intramuscular (IM) olanzapine in severely agitated patients. Methods This was an open-label multicenter 1-week observational study of IM olanzapine treatment in severely agitated inpatients and psychiatric emergency services with bipolar mania (n = 22) or schizophrenia (n = 52). Mean change from baseline to 2 h post-first injection (LOCF) in agitation was assessed by PANSS-Excited Component (PANSS-EC) (score range: 5–35 points) mean change from baseline to 15, 30, 45, 60, 90, and 120 min post-first injection, and visit-wise mean changes from mixed-model repeated measures analysis of variance. Kaplan–Meier survival curve analyses estimated time to categorical response (rating of ≤3 points each PANSS-EC item). Results Two hours post-injection of olanzapine (mean dose = 9.9 mg), patients exhibited mild calmness and agitation was significantly reduced by 19.2 ± 1.0 points (p

This study aims to confirm the initial pharmacogenetic finding observed within the clinical proof-of-concept trial of an enhanced response to treatment with pomaglumetad methionil (LY2140023 monohydrate) in Caucasian schizophrenia patients homozygous for T/T at single nucleotide polymorphism rs7330461 in the serotonin (5-hydroxytryptamine) 2A receptor gene compared to A/A homozygous patients. The effect of the rs7330461 genotype on the response to pomaglumetad methionil treatment was assessed in three additional clinical trials and in an integrated analysis. Overall, this study includes data from 1115 Caucasian patients for whom genotyping information for rs7330461 was available, consisting of 513 A/A homozygous, 466 A/T heterozygous and 136 T/T homozygous patients. Caucasian T/T homozygous patients showed significantly (p ≤ 0.05) greater improvement in Positive and Negative Syndrome Scale (PANSS) total scores during treatment with pomaglumetad methionil 40 mg twice daily compared to A/A homozygous patients. Additionally, T/T homozygous patients receiving pomaglumetad methionil had significantly (p ≤ 0.05) greater improvements in PANSS total scores compared to placebo and similar improvements as T/T homozygous patients receiving standard-of-care (SOC) treatment. The findings reported here in conjunction with prior reports show that in Caucasian patients with schizophrenia, the T/T genotype at rs7330461 is consistently associated with an increased treatment response to pomaglumetad methionil compared to the A/A genotype.

Background: The risk of persistent tardive dyskinesia (TD) was compared in patients with acute psychosis or agitation aged 55 years or older who were treated with olanzapine (OLZ) or conventional antipsychotic (CNV) drug therapy. Methods: Patients without TD were randomized to treatment with OLZ (2.5-20 mg/d; n = 150) or CNV (dosed per label; n = 143). Following a 6-week drug tapering/initiation period, patients without TD were treated with OLZ or CNV for up to 1 year. The a priori defined primary outcome end point was persistent TD defined as Abnormal Involuntary Movement Scale (AIMS) scores = 2 on at least 2 items or ≥3 on at least 1 item (items 1-7) lasting at least for 1 month (Criterion A). Post hoc analyses assessed persistent TD meeting the criterion of moderate severity defined as AIMS score ≥3 on at least 1 item persisting for 1 month (Criterion B) and probable TD defined as elevated AIMS scores (Criterion A or B) not persisting for 1 month. Treatment groups were compared using Kaplan-Meier curve with log-rank exact test. Results: On average, patients were 78 years of age; the predominant diagnosis was dementia (76.7% in the OLZ group and 82.5% in the CNV group). Approximately, 40.6% of patients in the CNV group received haloperidol. No significant difference in time to developing persistent TD was observed during treatment with OLZ or CNV (cumulative incidence: OLZ, 2.5% [95% confidence interval [95% CI]: 0.5-7.0]; CNV, 5.5% [95% CI: 2.1-11.6], P = .193). The exposure-adjusted event rates per 100 person-years were not significantly different between treatment groups: OLZ (2.7) and CNV (6.3; ratio: 0.420; 95% CI: 0.068-1.969). Post hoc analyses revealed a significantly lower risk of at least moderately severe persistent TD persisting for 1 month ( P = .012) and probable TD not persisting for 1 month (Criterion A, P = .030; Criterion B, P = .048) in OLZ-treated patients. For those patients without significant extrapyramidal symptoms at baseline, significantly more patients in the CNV treatment group developed treatment-emergent parkinsonism than for patients in the OLZ treatment group (CNV: 70%, 35 of 50 patients; OLZ 44%, 25 of 57 patients; P = .011). No significant difference between the groups was observed for treatment-emergent akathisia (CNV: 6%, 7 of 117 patients; OLZ: 10%, 13 of 130 patients; P = .351). Conclusion: The cumulative incidence of persistent TD was low and the risk of persistent TD did not differ significantly among predominantly older adult patients having dementia with acute psychosis or agitation treated with OLZ or CNV.

Antipsychotic treatment discontinuation can be used to measure overall treatment effectiveness. Our goal was to investigate differential treatment discontinuation comparing olanzapine with other atypical antipsychotics. A post hoc pooled analysis of 4 randomized, double-blind, 24- to 28-week schizophrenia clinical trials included 822 olanzapine-treated and 805 risperidone-, quetiapine-, or ziprasidone-treated patients. A checklist was used to record the reason for discontinuation. Treatment differences were assessed between olanzapine and the other 3 antipsychotics combined. Poor response/symptom worsening was the primary reason for discontinuation, regardless of medication. The rate of discontinuation due to poor response/symptom worsening significantly varied by treatment (olanzapine, 14.23%, vs. other atypical antipsychotics, 24.60%; P < 0.0001). The rate of discontinuation due to intolerability of medication did not significantly vary by treatment (olanzapine, 5.60%, vs. other atypical antipsychotics, 7.45%; P = 0.13). Consequent to the differential rates of discontinuation due to poor response/symptom worsening, the olanzapine-treated patients experienced a significantly greater likelihood of overall treatment completion (53.9% vs. 39.3%; P < 0.001) and a significantly longer duration of treatment (19.1 vs. 16.1 weeks; P < 0.0001) than other atypical-treated patients. The predominant reason for the significantly lower discontinuation rate of treatment for patients taking olanzapine compared with that of patients taking other atypical antipsychotics was the significantly higher dropout rates in other atypical antipsychotics because of poor response/symptom worsening.

This study compared the effects of olanzapine (OLZ) with those of quetiapine (QUE) for improving negative symptoms in patients diagnosed with schizophrenia or schizoaffective disorder who had prominent negative symptoms and marked deficits in social or occupational functioning. In this 6-month, multicenter, double-blind clinical trial, patients were randomized to treatment with OLZ (n = 171, 10-20 mg/d) or QUE (n = 175, 300-700 mg/d). Patients were treated at community mental health centers and assigned case managers who developed individualized psychosocial treatment plans. The primary efficacy measure was the reduction in negative symptoms using the Scale for the Assessment of Negative Symptoms. Secondary measures assessed changes in functioning, psychopathology, and treatment tolerability. Treatment with OLZ or QUE led to a significant reduction in negative symptoms, with no between-group difference (P = 0.09). Both treatment groups also showed significant improvement on most efficacy measures. Olanzapine-treated patients showed significantly greater improvement on positive symptoms and on several measures of functioning including Global Assessment of Functioning Scale, Quality of Life Instrumental Role domain, and level of effort in psychosocial or occupational rehabilitation programs. Significantly more OLZ-treated patients completed the study (52.6% OLZ, 37.7% QUE, P = 0.007). Treatment differences in safety were relatively small and not thought to be clinically relevant. Patients with schizophrenia who manifest prominent negative symptoms and marked functional deficits demonstrated significant improvement in negative symptoms after treatment with OLZ or QUE. Greater improvement in positive symptoms and a greater study completion rate may hold relevance to enhanced functional outcomes observed after OLZ therapy.

Summary This open-label, prospective, 4-month study in hyperprolactinemic patients with schizophrenia explored whether prolactin levels decrease after switching antipsychotic therapy to olanzapine. A secondary objective was to determine if reproductive morbidities and sexual dysfunction occurring with hyperprolactinemia improved with prolactin normalization. Clinically stable patients with schizophrenia, who had hyperprolactinemia defined as >18.8 ng/ml for males and >24.2 ng/ml for females, were randomized to: remain on current therapy ( n =27) or switch to olanzapine, 5–20 mg/day, ( n =27). Baseline prolactin levels in female patients randomized to receive olanzapine ( n =14) were 66.3±38.7 ng/ml and were 82.0±37.6 ( p =.32) in those remaining on their pre-study antipsychotic medication ( n =14). In male patients, baseline prolactin levels were 33.7±12.1 and 33.5±13.8 ng/ml ( p =.97), respectively, for those randomized to olanzapine ( n =13) or remaining on pre-study treatment ( n =13). At study end, patients switched to olanzapine experienced significant reductions in mean serum prolactin levels of 19.8±18.1 ng/ml in males ( p =.02), and 32.3±47.5 ng/ml in females ( p =.01), but prolactin continued to be elevated in patients who remained on pre-study antipsychotic treatment. After switching to olanzapine treatment, male patients experienced significantly ( p =.03) increased free testosterone levels but there were no significant improvements in total testosterone levels; some female patients experienced improved menstrual cycling, as well as resolution of galactorrhea and gynecomastia, and sexual functioning was significantly improved in both genders. Patients switched to olanzapine, as well as those remaining on their pre-study medication, maintained clinical stability, their symptoms continued to improve, although there were no significant between-treatment differences in improvement. Treatment-emergent adverse events did occur in both treatment groups; however, they were not significantly different between groups. Olanzapine-treated patients experienced significantly lower eosinophil counts and higher elevations in low-density lipoproteins and standing blood pressure than non-switched patients. Olanzapine treatment may offer sustained reduction in serum prolactin and improvement in sexual and reproductive comorbid symptoms in patients with schizophrenia who have treatment-emergent hyperprolactinemia.

ObjectivesThis randomized, open-label trial was designed to help inform antipsychotic treatment policies. It compared the 1-year cost-effectiveness of initial treatment with olanzapine (OLZ) (n = 229) versus a “fail-first” algorithm on conventional antipsychotics (then olanzapine if indicated) (CON) (n = 214); and versus initial treatment with risperidone (RIS) (n = 221).MethodsIndividuals with schizophrenia or schizoaffective disorder were recruited from May 1998 to September 2001. Clinical, functioning, and resource utilization data were collected at baseline and five postbaseline visits. Brief Psychiatric Rating Scale scores defined “clinical effectiveness;” Lehman Quality of Life Scale social relations scores defined “social effectiveness.”ResultsRequiring failure on less expensive antipsychotics before use of olanzapine did not result in total cost savings, despite significantly higher antipsychotic costs with OLZ. Total 1-year mean costs were $21,283 for CON; $20,891 for OLZ; and $21,347 for RIS (pair-wise comparisons nonsignificant). Intent-to-treat effectiveness comparisons (nonsignificant) were augmented by analyses that adjusted for duration on initial antipsychotic treatment, and by comparisons of patients remaining on initial antipsychotic treatment versus those who required switching. When accounting for differential switching rates (OLZ 0.14 vs. CON 0.53, P < 0.0001; vs. RIS 0.31, P < 0.0001), OLZ was significantly more effective than CON on clinical (P = 0.025) and social (P = 0.043) measures, and significantly more effective than RIS on the social (P = 0.002) measure. Further, patients initiated on an antipsychotic from which they needed to switch required additional resources for hospitalization (P = 0.036) and crisis services (P = 0.029).ConclusionsApproaches that integrate costs, effectiveness, and treatment patterns are important for providing optimal information regarding the value of first-line antipsychotic options for schizophrenia.

Weight gain is an important issue in the use of atypical antipsychotics, including olanzapine. A retrospective analysis of patterns of weight gain and possible covariates was performed for 1191 patients diagnosed with schizophrenia or schizoaffective disorder who were treated with olanzapine for up to 52 weeks. Patients were dichotomized into 2 main groups according to the percentage of body weight gained during the first 6 weeks of treatment with olanzapine: (1) patients who gained > or =7% of their body weight (Rapid Weight Gain Group [RWG]), and (2) patients who lost weight, gained no weight, or gained

Objective To describe the change in serum prolactin concentrations in elderly agitated nursing home patients with dementia who were newly initiated on olanzapine or switched to olanzapine treatment from either conventional antipsychotics or risperidone. Methods During an 8-week open-label olanzapine efficacy trial in elderly nursing home patients demonstrating clinically significant behavioral and psychological symptoms of dementia, serum prolactin concentrations were drawn on four occasions: at time of consent, following a washout period from previous therapy, midway through the study, and at endpoint. To assess post-hoc the effects of prolactin concentrations upon switching to olanzapine treatment, patients were divided into three different groups, based upon status at time of consent: those not taking antipsychotic medication, those taking any conventional antipsychotic, and those taking risperidone. Prolactin concentrations were assessed using a mixed-effect repeated-measures model. Symptom severity was measured using the Brief Psychiatric Rating Scale (BPRS), the Cohen-Mansfield Agitation Inventory (CMAI), the Clinical Global Impression (CGI)-Severity scale, and the Mini-Mental State Examination (MMSE), and the same repeated measures analysis was performed on these scales. Results Patients not on antipsychotic medication at study entry (29 females, 7 males) experienced a significant increase in prolactin concentration baseline to endpoint (P Conclusion Consistent with previous findings in younger patients, olanzapine appeared to be a prolactin-sparing antipsychotic medication in the elderly with only modest prolactin increases observed. In addition, patients who were receiving risperidone and then switched to olanzapine experienced a significant reduction in prolactin concentrations that was sustained over the 8-week treatment course with olanzapine. One possible explanation for olanzapine's relatively modest increase in prolactin is that, unlike conventionals or risperidone, olanzapine binds less tightly with the dopamine D2 receptor.

The objective of this study was to determine if the orally disintegrating tablet formulation of olanzapine, Zyprexa Zydis, would facilitate antipsychotic medication compliance in acutely ill, non-compliant patients. Eighty-five acutely ill patients with schizophrenia or schizoaffective disorder who met medication non-compliance criteria received open-label olanzapine orally disintegrating tablets (1020 mgd) for up to 6 wk. Improvement in medication compliance was assessed using various rating scales to measure changes in psychopathology, medication-taking and compliance attitudes, and nursing care burden. Safety variables were also measured. Significant improvement from baseline was demonstrated in the Positive and Negative Syndrome Scale total score at Week 1 and subsequently (p0.001). Significant improvement from baseline was also seen in various scales measuring medication compliance, attitude, and nursing care burden (p0.05). Olanzapine orally disintegrating tablets were well-tolerated. Olanzapine orally disintegrating tablets may benefit acutely ill, non-compliant schizophrenic patients by facilitating acceptance of active antipsychotic drug therapy.