Effect of diabetes on caregiver burden in an observational study of individuals with Alzheimer's disease.

BACKGROUND: The burden on caregivers of patients with Alzheimer's disease (AD) is associated with the patient's functional status and may also be influenced by chronic comorbid medical conditions, such as diabetes. This post-hoc exploratory analysis assessed whether comorbid diabetes in patients with AD affects caregiver burden, and whether caregivers with diabetes experience greater burden than caregivers without diabetes. Caregiver and patient healthcare resource use (HCRU) were also assessed. METHODS: Baseline data from the GERAS observational study of patients with AD and their caregivers (both n = 1495) in France, Germany and the UK were analyzed. Caregiver burden was assessed using the Zarit Burden Interview (ZBI). Caregiver time on activities of daily living (ADL: basic ADL; instrumental ADL, iADL) and supervision (hours/month), and caregiver and patient HCRU (outpatient visits, emergency room visits, nights hospitalized) were assessed using the Resource Utilization in Dementia instrument for the month before the baseline visit. Regression analyses were adjusted for relevant covariates. Time on supervision and basic ADL was analyzed using zero-inflated negative binomial regression. RESULTS: Caregivers of patients with diabetes (n = 188) were younger and more likely to be female (both p < 0.05), compared with caregivers of patients without diabetes (n = 1307). Analyses showed caregivers of patients with diabetes spent significantly more time on iADL (+16 %; p = 0.03; increases were also observed for basic ADL and total caregiver time but did not reach statistical significance) and had a trend towards increased ZBI score. Patients with diabetes had a 63 % increase in the odds of requiring supervision versus those without diabetes (p = 0.01). Caregiver and patient HCRU did not differ according to patient diabetes. Caregivers with diabetes (n = 127) did not differ from those without diabetes (n = 1367) regarding burden/time, but caregivers with diabetes had a 91 % increase in the odds of having outpatient visits (p = 0.01). CONCLUSIONS: This cross-sectional analysis found caregiver time on iADL and supervision was higher for caregivers of patients with AD and diabetes versus without diabetes, while HCRU was unaffected by patient diabetes. Longitudinal analyses assessing change in caregiver burden over time by patient diabetes status may help clarify the cumulative impact of diabetes and AD dementia on caregiver burden.

Comparison of olanzapine long-acting injection and oral olanzapine: a 2-year, randomized, open-label study in outpatients with schizophrenia.

We compared long-term treatment effectiveness of monthly olanzapine long-acting injection (LAI) with that of oral olanzapine. Outpatients with 2 or more episodes of psychotic worsening in the past 24 months with Positive and Negative Syndrome Scale total score of lower than 70 were randomized to 405 mg/4 weeks of olanzapine LAI (n = 264) or 10 mg/d of oral olanzapine (n = 260) for 2 years of open-label treatment. Dosing thereafter was flexible (150-405 mg/4 weeks of LAI vs 5-20 mg/d of oral). Primary outcome was time to all-cause discontinuation. At baseline, patients were clinically stable (mean Positive and Negative Syndrome Scale total score of 57). Seventeen percent of patients had been psychiatrically hospitalized in the previous 6 months, and 4.6% were rated nonadherent in the month before study entry. The groups did not differ significantly in median time to all-cause discontinuation (645 days for LAI, 678 days for oral; P = 0.61), discontinuation rate (53.8% for LAI, 51.2% for oral; P = 0.60), or relapse rate (20.1% for LAI, 18.5% for oral; P = 0.66). Postbaseline psychiatric hospitalization rate was low for both groups (7.6% for LAI, 9.2% for oral), but mean hospitalization duration was significantly longer for oral patients (1.80 days [20 for those hospitalized] vs 0.43 days [6 for those hospitalized], P = 0.02). There were no clinically significant group differences in adverse events or safety measures. No post-injection delirium/sedation syndrome events occurred. In conclusion, olanzapine LAI and oral olanzapine were similarly effective and well tolerated for up to 2 years of treatment in patients with schizophrenia. Treatment discontinuation for olanzapine LAI was similar to that of oral olanzapine, despite the 3-hour post-injection observation period and other precautionary procedures related to risk of post-injection delirium/sedation syndrome.

Empirically driven definitions of "good," "moderate," and "poor" levels of functioning in the treatment of schizophrenia.

PURPOSE: This study used an empirical approach to identify and validate the classification of patients with schizophrenia in "good," "moderate," or "poor" functioning groups based on the assessment of functional measures. METHODS: Using data from a study of schizophrenia outpatients, patients were classified into functional groups using cluster analysis based on the Heinrich-Carpenter Quality of Life Scale (QLS), the 36-item Short-Form Health Survey (SF-36) Mental Component Summary Score, and a productivity measure. A three-cluster solution was chosen. Concurrent, convergent, and discriminant validity were assessed. Criteria for classifying patient functioning as "good," "moderate," or "poor" were established using classification and regression tree analysis. RESULTS: The three clusters consistently differentiated patients on the QLS, SF-36 Mental Component Summary Score, and productivity measure. The clusters also differed on other functional measures and were concordant with previous functional classifications. Concurrent, convergent, and discriminant validity were good. "Good" functioning was identified as a QLS total score ≥ 84.5; "moderate" and "poor" functioning were separated by a cutoff score of 15.5 on the QLS intrapsychic foundation domain. Sensitivity ranged from 86 to 93 % and specificity from 89 to 99 %. CONCLUSIONS: The heterogeneity in functioning of schizophrenia patients can be classified reliably in an empirical manner using specific cutoff scores on commonly used functional measures.

Predictors of psychiatric hospitalization during 6 months of maintenance treatment with olanzapine long-acting injection: post hoc analysis of a randomized, double-blind study.

BACKGROUND: Hospitalization is a costly and distressing event associated with relapse during schizophrenia treatment. No information is available on the predictors of psychiatric hospitalization during maintenance treatment with olanzapine long-acting injection (olanzapine-LAI) or how the risk of hospitalization differs between olanzapine-LAI and oral olanzapine. This study aimed to identify the predictors of psychiatric hospitalization during maintenance treatment with olanzapine-LAI and assessed four parameters: hospitalization prevalence, incidence rate, duration, and the time to first hospitalization. Olanzapine-LAI was also compared with a sub-therapeutic dose of olanzapine-LAI and with oral olanzapine. METHODS: This was a post hoc exploratory analysis of data from a randomized, double-blind study comparing the safety and efficacy of olanzapine-LAI (pooled active depot groups: 405 mg/4 weeks, 300 mg/2 weeks, and 150 mg/2 weeks) with oral olanzapine and sub-therapeutic olanzapine-LAI (45 mg/4 weeks) during 6 months' maintenance treatment of clinically stable schizophrenia outpatients (n=1064). The four psychiatric hospitalization parameters were analyzed for each treatment group. Within the olanzapine-LAI group, patients with and without hospitalization were compared on baseline characteristics. Logistic regression and Cox's proportional hazards models were used to identify the best predictors of hospitalization. Comparisons between the treatment groups employed descriptive statistics, the Kaplan-Meier estimator and Cox's proportional hazards models. RESULTS: Psychiatric hospitalization was best predicted by suicide threats in the 12 months before baseline and by prior hospitalization. Compared with sub-therapeutic olanzapine-LAI, olanzapine-LAI was associated with a significantly lower hospitalization rate (5.2% versus 11.1%, p < 0.01), a lower mean number of hospitalizations (0.1 versus 0.2, p = 0.01), a shorter mean duration of hospitalization (1.5 days versus 2.9 days, p < 0.01), and a similar median time to first hospitalization (35 versus 60 days, p = 0.48). Olanzapine-LAI did not differ significantly from oral olanzapine on the studied hospitalization parameters. CONCLUSIONS: In clinically stable schizophrenia outpatients receiving olanzapine-LAI maintenance treatment, psychiatric hospitalization was best predicted by a history of suicide threats and prior psychiatric hospitalization. Olanzapine-LAI was associated with a significantly lower incidence of psychiatric hospitalization and shorter duration of hospitalization compared with sub-therapeutic olanzapine-LAI. Olanzapine-LAI did not differ significantly from oral olanzapine on hospitalization parameters. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00088491.

The longitudinal interplay between negative and positive symptom trajectories in patients under antipsychotic treatment: a post hoc analysis of data from a randomized, 1-year pragmatic trial.

BACKGROUND: Schizophrenia is a highly heterogeneous disorder with positive and negative symptoms being characteristic manifestations of the disease. While these two symptom domains are usually construed as distinct and orthogonal, little is known about the longitudinal pattern of negative symptoms and their linkage with the positive symptoms. This study assessed the temporal interplay between these two symptom domains and evaluated whether the improvements in these symptoms were inversely correlated or independent with each other. METHODS: This post hoc analysis used data from a multicenter, randomized, open-label, 1-year pragmatic trial of patients with schizophrenia spectrum disorder who were treated with first- and second-generation antipsychotics in the usual clinical settings. Data from all treatment groups were pooled resulting in 399 patients with complete data on both the negative and positive subscale scores from the Positive and Negative Syndrome Scale (PANSS). Individual-based growth mixture modeling combined with interplay matrix was used to identify the latent trajectory patterns in terms of both the negative and positive symptoms. Pearson correlation coefficients were calculated to examine the relationship between the changes of these two symptom domains within each combined trajectory pattern. RESULTS: We identified four distinct negative symptom trajectories and three positive symptom trajectories. The trajectory matrix formed 11 combined trajectory patterns, which evidenced that negative and positive symptom trajectories moved generally in parallel. Correlation coefficients for changes in negative and positive symptom subscale scores were positive and statistically significant (P < 0.05). Overall, the combined trajectories indicated three major distinct patterns: (1) dramatic and sustained early improvement in both negative and positive symptoms (n = 70, 18%), (2) mild and sustained improvement in negative and positive symptoms (n = 237, 59%), and (3) no improvement in either negative or positive symptoms (n = 82, 21%). CONCLUSIONS: This study of symptom trajectories over 1 year shows that changes in negative and positive symptoms were neither inversely nor independently related with each other. The positive association between these two symptom domains supports the notion that different symptom domains in schizophrenia may depend on each other through a unified upstream pathological disease process.

Characteristics of patients misdiagnosed with Alzheimer's disease and their medication use: an analysis of the NACC-UDS database.

BACKGROUND: This study compared individuals whose clinical diagnosis of Alzheimer's disease (AD) matched or did not match neuropathologic results at autopsy on clinical and functional outcomes (cognitive impairment, functional status and neuropsychiatric symptoms). The study also assessed the extent of potentially inappropriate medication use (using potentially unnecessary medications or potentially inappropriate prescribing) among misdiagnosed patients. METHODS: Longitudinal data from the National Alzheimer's Coordinating Center Uniform Data Set (NACC-UDS, 2005-2010) and corresponding NACC neuropathological data were utilized to compare 88 misdiagnosed and 438 accurately diagnosed patients. RESULTS: Following adjustment of sociodemographic characteristics, the misdiagnosed were found to have less severe cognitive and functional impairment. However, after statistical adjustment for sociodemographics, dementia severity level, time since onset of cognitive decline and probable AD diagnosis at baseline, the groups significantly differed on only one outcome: the misdiagnosed were less likely to be depressed/dysphoric. Among the misdiagnosed, 18.18% were treated with potentially inappropriate medication. An additional analysis noted this rate could be as high as 67.10%. CONCLUSIONS: Findings highlight the importance of making an accurate AD diagnosis to help reduce unnecessary treatment and increase appropriate therapy. Additional research is needed to demonstrate the link between potentially inappropriate treatment and adverse health outcomes in misdiagnosed AD patients.

Updating and confirming an industry-sponsored pharmacoeconomic model: comparing two antipsychotics in the treatment of schizophrenia.

OBJECTIVE: This study updated a 2001 decision economic model that used indirect data and confirmed its findings by developing a new cost-effectiveness model by using now available head-to-head data. The models compared olanzapine with ziprasidone in the treatment of schizophrenia in the United States. METHODS: A decision analytic modeling approach was used to estimate annual health-care costs and health outcomes, incorporating events such as response, relapse, and suicide. Patients without response to first-line treatment switched to the other comparator. Decision tree probabilities were extracted from head-to-head studies and other published clinical literature. Direct health-care costs and quality-adjusted life-years (QALYs) were estimated on the basis of resource use and utility weights for initial and relapse episodes, maintenance therapy, and extended episodes of illness. Disutilities associated with treatment-emergent adverse events were included. RESULTS: Consistent with the 2001 model, this model found that first-line treatment with olanzapine is associated with fewer hospital days, fewer days with extrapyramidal symptoms, and higher QALYs than is first-line treatment with ziprasidone. Total costs were lower for the olanzapine pathway ($70,232-$72,776 vs. $73,086-$73,310 in the Positive and Negative Syndrome Scale analysis) due to the cost savings associated with reduced health-care resource use. The incremental cost per QALY gained indicated that the olanzapine pathway dominated the ziprasidone pathway. CONCLUSIONS: Decision analytic models should be continuously assessed against new data. This case study shows that incorporating new data confirmed results of a previously published model in which olanzapine was associated with better expected health outcomes and lower total health-care costs than was ziprasidone.

Construct validity of 2 measures to assess reasons for antipsychotic discontinuation and continuation from patients' and clinicians' perspectives in a clinical trial.

BACKGROUND: Little is known about the specific reasons for antipsychotic discontinuation or continuation from patients' or clinicians' perspectives. This study aimed to assess the construct validity of 2 new measures of the Reasons for Antipsychotic Discontinuation/Continuation (RAD): RAD-I (a structured interview assessing the patient's perspective) and RAD-Q (a questionnaire assessing the clinician's perspective). METHODS: Data were used from a 12-week antipsychotic trial of schizophrenia patients in which the RAD was administered at study entry and at study completion (or discontinuation). Construct validity was assessed through comparisons of RAD responses, clinicians' responses to a standard patient disposition form identifying reasons for patient's study discontinuation, and several standard psychiatric measures. Percent agreement quantified the correspondence between patient and clinician scores. RESULTS: Patients indicating lack of improvement/worsening of positive symptoms as a 'somewhat' to 'primary' reason for medication discontinuation had statistically significantly less improvement in Positive and Negative Syndrome Scale positive score than patients not reporting these as a reason (concurrent validity). Similar results were observed for the RAD negative symptom, functional, social support, and adherence items, whereas the mood and cognitive items were not significantly associated with change scores on standard psychiatric measures. Responses to the RAD were also weakly associated with variables that theoretically should not be related to them (divergent validity). Level of agreement between the clinician- and patient-rated RAD scores was high (60%-100%). CONCLUSIONS: Initial validation of the RAD suggests that the instruments are valid tools for gathering detailed information regarding reasons for antipsychotic discontinuation and continuation from patients' and clinicians' perspectives.

Long-term healthcare costs and functional outcomes associated with lack of remission in schizophrenia: a post-hoc analysis of a prospective observational study.

BACKGROUND: Little is known about the long-term outcomes for patients with schizophrenia who fail to achieve symptomatic remission. This post-hoc analysis of a 3-year study compared the costs of mental health services and functional outcomes between individuals with schizophrenia who met or did not meet cross-sectional symptom remission at study enrollment. METHODS: This post-hoc analysis used data from a large, 3-year prospective, non-interventional observational study of individuals treated for schizophrenia in the United States conducted between July 1997 and September 2003. At study enrollment, individuals were classified as non-remitted or remitted using the Schizophrenia Working Group Definition of symptom remission (8 core symptoms rated as mild or less). Mental health service use was measured using medical records. Costs were based on the sites' medical information systems. Functional outcomes were measured with multiple patient-reported measures and the clinician-rated Quality of Life Scale (QLS). Symptoms were measured using the Positive and Negative Syndrome Scale (PANSS). Outcomes for non-remitted and remitted patients were compared over time using mixed effects models for repeated measures or generalized estimating equations after adjusting for multiple baseline characteristics. RESULTS: At enrollment, most of the 2,284 study participants (76.1%) did not meet remission criteria. Non-remitted patients had significantly higher PANSS total scores at baseline, a lower likelihood of being Caucasian, a higher likelihood of hospitalization in the previous year, and a greater likelihood of a substance use diagnosis (all p < 0.05). Total mental health costs were significantly higher for non-remitted patients over the 3-year study (p = 0.008). Non-remitted patients were significantly more likely to be victims of crime, exhibit violent behavior, require emergency services, and lack paid employment during the 3-year study (all p < 0.05). Non-remitted patients also had significantly lower scores on the QLS, SF-12 Mental Component Summary Score, and Global Assessment of Functioning during the 3-year study. CONCLUSIONS: In this post-hoc analysis of a 3-year prospective observational study, the failure to achieve symptomatic remission at enrollment was associated with higher subsequent healthcare costs and worse functional outcomes. Further examination of outcomes for schizophrenia patients who fail to achieve remission at initial assessment by their subsequent clinical status is warranted.

Antipsychotic monotherapy and polypharmacy in the treatment of outpatients with schizophrenia in the European Schizophrenia Outpatient Health Outcomes Study.

This post hoc study used data from the naturalistic Schizophrenia Outpatient Health Outcomes study, assessing the factors associated with starting antipsychotic monotherapy and the annual rate and duration of antipsychotic monotherapy among patients initiating atypical antipsychotics (N = 6866). Descriptive and regression analyses were used. Factors associated with starting antipsychotic monotherapy at baseline were antipsychotic treatment for the first time, shorter duration of illness, less severe illness, and better social functioning. Baseline monotherapy was maintained throughout 12 months by 63.2% of patients and was significantly greater for olanzapine (66.8%) than for risperidone (62.8%), quetiapine (43.4%), or amisulpride (52.6%) (all p ≤ 0.01). The predicted mean number of days on baseline monotherapy was significantly longer for olanzapine than for risperidone, quetiapine, or amisulpride (all p < 0.01). Initiation of antipsychotic monotherapy at baseline is associated with select baseline patient characteristics. Olanzapine was found to have the highest monotherapy rate and the longest duration of maintained monotherapy, followed by risperidone, amisulpride, and quetiapine.

Improved outcomes following a switch to olanzapine treatment from risperidone treatment in a 1-year naturalistic study of schizophrenia patients in Japan.

AIMS: This study assessed clinical and functional outcomes following a switch from risperidone to olanzapine in a 1-year naturalistic study of schizophrenia patients in Japan. METHODS: We used data from a large 1-year prospective, multicenter, observational non-interventional study of individuals who were initiated on olanzapine for the treatment of schizophrenia in Japan. Current analyses focused on patients who were switched at study entry from risperidone to olanzapine (n = 258). Repeated measures analysis was employed to assess outcomes on validated measures. RESULTS: At study entry, 45% were inpatients and 55% outpatients. Participants were in their early 40s with mean illness duration of 14 years. Approximately half were male. Most were switched from risperidone to olanzapine due to poor medication efficacy (67.8%) rather than medication intolerability (29.1%). Most patients (67.8%) completed the 1-year study. Patients experienced clinically and statistically significant (P < 0.05) improvements in global symptom severity, positive, negative, depressive, and cognitive symptoms, health-related quality of life, and paid work rates. Most patients (59.2%) demonstrated treatment response to olanzapine and 43.4% experienced symptom remission. Mean weight gain was 2.19 kg, with one-third of patients (33.3%) experiencing clinically significant weight gain (≥7%). CONCLUSIONS: In this 1-year naturalistic study, inpatients and outpatients who were switched from risperidone to olanzapine experienced clinically and statistically significant improvements in their clinical and functional outcomes. One-third of all patients experienced clinically significant weight gain. Current findings highlight the favorable benefit-to-risk profile of switching to olanzapine therapy following treatment failure on risperidone among patients with schizophrenia in Japan.

Development of a clinician questionnaire and patient interview to assess reasons for antipsychotic discontinuation.

Time to treatment discontinuation and rates of discontinuation are commonly used when evaluating effectiveness of antipsychotic medication. However, less is known about reasons for discontinuation. The purpose of this study was to develop two measures of reasons for discontinuation or continuation of antipsychotics for the treatment of schizophrenia. Based on literature review, a patient interview pilot study, and expert panel input, two measures were drafted: the clinician-reported Reasons for Antipsychotic Discontinuation/Continuation Questionnaire (RAD-Q) and the patient-reported Reasons for Antipsychotic Discontinuation/Continuation Interview (RAD-I). Patients and clinicians completed the draft measures and structured cognitive debriefing interviews. For the draft instruments, reasons for discontinuation/continuation were divided into 3 categories: therapeutic benefits (positive symptoms, negative symptoms, mood, cognition, functional status), adverse events, and reasons other than direct effects of the medication (e.g., cost, inadequate social support). In cognitive debriefings, 10 clinicians and 15 patients indicated that the RAD-Q and RAD-I were clear, easy to complete, and comprehensive. Clinicians and patients suggested minor revisions, and the instruments were revised accordingly. The RAD-Q and RAD-I appear to be useful instruments for assessing reasons for antipsychotic discontinuation and continuation. The next step is a psychometric evaluation of the measures in a larger sample.

Early response to antipsychotic therapy as a clinical marker of subsequent response in the treatment of patients with first-episode psychosis.

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.

Sustained favorable long-term outcome in the treatment of schizophrenia: a 3-year prospective observational study.

BACKGROUND: This study of chronically ill patients with schizophrenia aimed to identify patients who achieve sustained favorable long-term outcome - when the outcome incorporates severity of symptoms, level of functioning, and use of acute care services - and to identify the best baseline predictors of achieving this sustained favorable long-term outcome. METHODS: Using data from the United States Schizophrenia Care and Assessment Program (US-SCAP) (N = 2327), a large 3-year prospective, multisite, observational study of individuals treated for schizophrenia in the US, a hierarchical cluster analysis was performed to group patients based upon baseline symptom severity. Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS) scores, level of functioning, and use of acute care services. Level of functioning reflected patient-reported productivity and clinician-rated occupational role functioning. Use of acute care services reflected self-reported psychiatric hospitalization and emergency service use. Change of health state was determined over the 3-year period. A patient was classified as having a sustained favorable long-term outcome if their health state values had the closest distance to the defined "best baseline cluster" at each point over the length of the study. Stepwise logistic regression was used to determine baseline predictors of sustained favorable long-term outcome. RESULTS: At baseline, 5 distinct health state clusters were identified, ranging from "best" to "worst." Of 1635 patients with sufficient data, only 157 (10%) experienced sustained favorable long-term outcome during the 2-years postbaseline. The baseline predictors associated with sustained favorable long-term outcome included better quality of life, more daily activities, patient-reported clearer thinking from medication, better global functioning, being employed, not being a victim of a crime, not having received individual therapy, and not having received help with shopping and leisure activities. CONCLUSIONS: Only a small percentage of patients achieved sustained favorable long-term outcome in this study, suggesting there continues to be a great need for improvement in the treatment of schizophrenia. Findings suggest that clinicians could make early projections of health states and identify those patients more likely to achieve favorable long-term outcomes enabling early therapeutic interventions to enhance benefits for patients.

Change in level of productivity in the treatment of schizophrenia with olanzapine or other antipsychotics.

BACKGROUND: When treating schizophrenia, improving patients' productivity level is a major goal considering schizophrenia is a leading cause of functional disability. Productivity level has been identified as the most preferred treatment outcome by patients with schizophrenia. However, little has been done to systematically investigate productivity levels in schizophrenia. We set out to better understand the change in productivity level among chronically ill patients with schizophrenia treated with olanzapine compared with other antipsychotic medications. We also assessed the links between productivity level and other clinical outcomes. METHODS: This post hoc analysis used data from 6 randomized, double-blind clinical trials of patients with schizophrenia or schizoaffective disorder, with each trial being of approximately 6 months duration. Change in productivity level was compared between olanzapine-treated patients (HGBG, n = 172; HGHJ, n = 277; HGJB, n = 171; HGLB, n = 281; HGGN, n = 159; HGDH, n = 131) and patients treated with other antipsychotic medications (separately vs. haloperidol [HGGN, n = 97; HGDH, n = 132], risperidone [HGBG, n = 167; HGGN, n = 158], quetiapine [HGJB, n = 175], ziprasidone [HGHJ, n = 271] and aripiprazole [HGLB, n = 285]). Productivity was defined as functional activities/work including working for pay, studying, housekeeping and volunteer work. Productivity level in the prior 3 months was assessed on a 5-point scale ranging from no useful functioning to functional activity/work 75% to 100% of the time. RESULTS: Chronically ill patients treated with olanzapine (OLZ) experienced significantly greater improvement in productivity when compared to patients treated with risperidone (RISP) (OLZ = 0.22 ± 1.19, RISP = -0.03 ± 1.17, p = 0.033) or ziprasidone (ZIP) (OLZ = 0.50 ± 1.38, ZIP = 0.25 ± 1.27, p = 0.026), but did not significantly differ from the quetiapine, aripiprazole or haloperidol treatment groups. Among first episode patients, OLZ therapy was associated with greater improvements in productivity levels compared to haloperidol (HAL), during the acute phase (OLZ = -0.31 ± 1.59, HAL = -0.69 ± 1.56, p = 0.011) and over the long-term (OLZ = 0.10 ± 1.50, HAL = -0.32 ± 1.91, p = 0.008). Significantly more chronically ill and first episode patients treated with olanzapine showed moderately high (>50%-75% of the time) and high levels of productivity (>75%-100% of the time) at endpoint, when compared to risperidone or haloperidol-treated patients (p < .05), respectively. Higher productivity level was associated with significantly higher study completion rates and better scores on the positive, negative, disorganized thoughts, hostility and depression subscales of the Positive and Negative Symptom Scale (PANSS). CONCLUSIONS: Some antipsychotic medications significantly differed in beneficial impact on productivity level in the long-term treatment of patients with schizophrenia. Findings further highlight the link between clinical and functional outcomes, showing significant associations between higher productivity, lower symptom severity and better persistence on therapy. TRIAL REGISTRATION: clinicaltrials.gov identifier NCT00088049; NCT00036088.

Identification of early changes in specific symptoms that predict longer-term response to atypical antipsychotics in the treatment of patients with schizophrenia.

BACKGROUND: To identify a simple decision tree using early symptom change to predict response to atypical antipsychotic therapy in patients with (Diagnostic and Statistical Manual, Fourth Edition, Text Revised) chronic schizophrenia. METHODS: Data were pooled from moderately to severely ill patients (n = 1494) from 6 randomized, double-blind trials (N = 2543). Response was defined as a ≥ 30% reduction in Positive and Negative Syndrome Scale (PANSS) Total score by Week 8 of treatment. Analyzed predictors were change in individual PANSS items at Weeks 1 and 2. A decision tree was constructed using classification and regression tree (CART) analysis to identify predictors that most effectively differentiated responders from non-responders. RESULTS: A 2-branch, 6-item decision tree was created, producing 3 distinct groups. First branch criterion was a 2-point score decrease in at least 2 of 5 PANSS positive items (Week 2). Second branch criterion was a 2-point score decrease in the PANSS excitement item (Week 2). "Likely responders" met the first branch criteria; "likely non-responders" did not meet first or second criterion; "not predictable" patients did not meet the first but did meet the second criterion. Using this approach, response to treatment could be predicted in most patients (92%) with high positive predictive value (79%) and high negative predictive value (75%). Predictive findings were confirmed through analysis of data from 2 independent trials. CONCLUSIONS: Using a data-driven approach, we identified decision rules using early change in the scores of selected PANSS items to accurately predict longer-term treatment response or non-response to atypical antipsychotic therapy. This could lead to development of a simple quantitative evaluation tool to help guide early treatment decisions. TRIAL REGISTRATION: This is a retrospective, non-intervention study in which pooled results from 6 previously published reports were analyzed; thus, clinical trial registration is not required.

The relationship, structure and profiles of schizophrenia measurements: a post-hoc analysis of the baseline measures from a randomized clinical trial.

BACKGROUND: To fully assess the various dimensions affected by schizophrenia, clinical trials often include multiple scales measuring various symptom profiles, cognition, quality of life, subjective well-being, and functional impairment. In this exploratory study, we characterized the relationships among six clinical, functional, cognitive, and quality-of-life measures, identifying a parsimonious set of measurements. METHODS: We used baseline data from a randomized, multicenter study of patients diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder who were experiencing an acute symptom exacerbation (n = 628) to examine the relationship among several outcome measures. These measures included the Positive and Negative Syndrome Scale (PANSS), Montgomery-Asberg Depression Rating Scale (MADRS), Brief Assessment of Cognition in Schizophrenia Symbol Coding Test, Subjective Well-being Under Neuroleptics Scale Short Form (SWN-K), Schizophrenia Objective Functioning Instrument (SOFI), and Quality of Life Scale (QLS). Three analytic approaches were used: 1) path analysis; 2) factor analysis; and 3) categorical latent variable analysis. In the optimal path model, the SWN-K was selected as the final outcome, while the SOFI mediated the effect of the exogenous variables (PANSS, MADRS) on the QLS. RESULTS: The overall model explained 47% of variance in QLS and 17% of the variance in SOFI, but only 15% in SWN-K. Factor analysis suggested four factors: "Functioning," "Daily Living," "Depression," and "Psychopathology." A strong positive correlation was observed between the SOFI and QLS (r = 0.669), and both the QLS and SOFI loaded on the "Functioning" factor, suggesting redundancy between these scales. The measurement profiles from the categorical latent variable analysis showed significant variation in functioning and quality of life despite similar levels of psychopathology. CONCLUSIONS: Researchers should consider collecting PANSS, SOFI, and SWN-K in their trials. This would allow a broad spectrum of assessments that would have the ability to capture a wide range of treatment outcomes and allow for a rich characterization of the subgroups involved. Additional research is needed to identify the critical cognitive measures. CLINICAL TRIALS REGISTRATION: Predicting Response to Risperidone Treatment Through Identification of Early-onset of Antipsychotic Drug Action in SchizophreniaClinicalTrials.gov identifier: NCT00337662; http://www.clinicaltrials.gov/

Early response predicts subsequent response to olanzapine long-acting injection in a randomized, double-blind clinical trial of treatment for schizophrenia.

BACKGROUND: In patients with schizophrenia, early non-response to oral antipsychotic therapy robustly predicts subsequent non-response to continued treatment with the same medication. This study assessed whether early response predicted later response when using a long-acting injection (LAI) antipsychotic. METHODS: Data were taken from an 8-week, randomized, double-blind, placebo-controlled study of olanzapine LAI in acutely ill patients with schizophrenia (n = 233). Early response was defined as ≥ 30% improvement from baseline to Week 4 in Positive and Negative Syndrome Scale (PANSS0-6) Total score. Subsequent response was defined as ≥ 40% baseline-to-endpoint improvement in PANSS0-6 Total score. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and predictive accuracy were calculated. Clinical and functional outcomes were compared between Early Responders and Early Non-responders. RESULTS: Early response/non-response to olanzapine LAI predicted later response/non-response with high sensitivity (85%), specificity (72%), PPV (78%), NPV (80%), and overall accuracy (79%). Compared to Early Non-responders, Early Responders had significantly greater improvement in PANSS0-6 Total scores at all time points and greater baseline-to-endpoint improvement in PANSS subscale scores, Quality of Life Scale scores, and Short Form-36 Health Survey scores (all p ≤ .01). Among Early Non-responders, 20% demonstrated response by Week 8. Patients who lacked early improvement (at Week 4) in Negative Symptoms and Disorganized Thoughts were more likely to continue being non-responders at Week 8. CONCLUSIONS: Among acutely ill patients with schizophrenia, early response predicted subsequent response to olanzapine LAI. Early Responders experienced significantly better clinical and functional outcomes than Early Non-responders. Findings are consistent with previous research on oral antipsychotics. CLINICAL TRIALS REGISTRY: F1D-MC-HGJZ: Comparison of Intramuscular Olanzapine Depot With Placebo in the Treatment of Patients With Schizophrenia http://clinicaltrials.gov/ct2/show/NCT00088478?term=olanzapine+depot&rank=3Registry identifier - NCT00088478.

Treatment response trajectories and their antecedents in recent-onset psychosis: a 2-year prospective study.

BACKGROUND: The extent of heterogeneity in antipsychotic treatment response for over extended period is unclear. This study aimed to quantify treatment response trajectories and their characteristics up to 2 years in recent-onset psychosis. METHOD: Participants were from a double-blind randomized controlled trial of recent-episode psychosis (N = 263). Recurrent Positive and Negative Syndrome Scale (PANSS) administrations were used to index treatment response trajectories for up to 2 years. Trajectories were calculated with mixed-mode latent class regression modeling from which groups were derived. Group differences were examined on sex, age of first admission, duration of untreated psychosis, premorbid functioning, diagnoses of substance abuse and schizophrenia, and cognitive functioning. RESULTS: Five trajectories based on PANSS total scores were identified at 2 years. In the trajectory group (23.1%) with the most improvement, approximately 62% met the PANSS 30% change criteria. Logistic regression modeling indicated that membership in the trajectory with the most improvement was significantly (P < 0.05) predicted by absence of a diagnosis of schizophrenia, better premorbid functioning, and higher cognitive scores. Membership in the trajectory with the least improvement was significantly predicted by higher PANSS baseline scores. CONCLUSIONS: Based on clinical trial data, treatment response in early episode psychosis seems to be characterized by amelioration and ongoing change. Premorbid functioning, cognitive functioning, and early symptom severity have prognostic value in predicting treatment response trajectories. Across trajectory studies, approximately 16% of patients experience a dramatic treatment response trajectory characterized by approximately a 60% to 80% symptom reduction.

Early onset of antipsychotic action in schizophrenia: evaluating the possibility of shorter acute efficacy trials.

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.