Cedric O'Gorman

Determinants of different aspects of everyday outcome in schizophrenia: The roles of negative symptoms, cognition, and functional capacity.

Cognition, negative symptoms, and depression are potential predictors of disability in schizophrenia. We present analyses of pooled data from four separate studies (all n>169; total n=821) that assessed differential aspects of disability and their potential determinants. We hypothesized that negative symptoms would predict social outcomes, but not vocational functioning or everyday activities and that cognition and functional capacity would predict vocational functioning and everyday activities but not social outcomes. The samples were rated by clinician informants for their everyday functioning in domains of social and vocational outcomes, and everyday activities, examined with assessments of cognition and functional capacity, rated clinically with the Positive and Negative Syndrome Scale (PANSS) and self-reporting depression. We computed a model that tested the hypotheses described above and compared it to a model that predicted that negative symptoms, depression, cognition, and functional capacity had equivalent influences on all aspects of everyday functioning. The former, specific relationship model fit the data adequately and we subsequently confirmed a similar fit within all four samples. Analyses of the relative goodness of fit suggested that this specific model fit the data better than the more general, equivalent influence predictor model. We suggest that treatments aimed at cognition may not affect social functioning as much as other aspects of disability, a finding consistent with earlier research on the treatment of cognitive deficits in schizophrenia, while negative symptoms predicted social functioning. These relationships are central features of schizophrenia and treatment efforts should be aimed accordingly.

Effects of Oral Ziprasidone and Oral Haloperidol on QTc Interval in Patients with Schizophrenia or Schizoaffective Disorder

Study Objective. To characterize the effect of oral ziprasidone and haloperidol on the corrected QT (QTc) interval under steady‐state conditions.

Effects of high-dose ziprasidone and haloperidol on the QTc interval after intramuscular administration: A randomized, single-blind, parallel-group study in patients with schizophrenia or schizoaffective disorder

BACKGROUND Antipsychotic agents have been associated with a prolonged QT interval. Data on the effects of ziprasidone and haloperidol on the QTc interval are lacking. OBJECTIVE This study aimed to characterize the effects of 2 high-dose intramuscular injections of ziprasidone and haloperidol on the QTc interval at T(max). METHODS This randomized, single-blind study enrolled patients with schizophrenia or schizoaffective disorder in whom long-term antipsychotic therapy was indicated. Patients were randomized to receive 2 high-dose intramuscular injections of ziprasidone (20 and 30 mg) or haloperidol (7.5 and 10 mg) separated by 4 hours. The primary outcome measure was the mean change from baseline in QTc at the T(max) of each injection. Each dose administration was followed by serial ECG and blood sampling for pharmacokinetic determinations. Twelve-lead ECG data were obtained immediately before and at predetermined times after injections. ECG tracings were read by a blinded central reader. Blood samples were obtained immediately before and after injections. Point estimates and 95% CIs for mean QTc and changes from baseline in QTc were estimated. No between-group hypothesis tests were conducted. For the assessments of tolerability and safety profile, patients underwent physical examination, including measurement of vital signs, clinical laboratory evaluation, and monitoring for adverse events (AEs) using spontaneous reporting. RESULTS A total of 59 patients were assigned to treatment, and 58 received study medication (ziprasidone, 31 patients; haloperidol, 27; age range, 21-72 years; 79% male). After the first injection, mean (95% CI) changes from baseline were 4.6 msec (0.4-8.9) with ziprasidone (n = 25) and 6.0 msec (1.4-10.5) with haloperidol (n = 24). After the second injection, these values were 12.8 msec (6.7-18.8) and 14.7 msec (10.2-19.2), respectively. Mild and transient changes in heart rate and blood pressure were observed with both treatments. None of the patients had a QTc interval >480 msec. Two patients in the ziprasidone group experienced QTc prolongation >450 msec (457 and 454 msec) and QTc changes that exceeded 60 msec (62 and 76 msec) relative to the time-matched baseline values. With haloperidol, QTc interval values were <450 msec with no changes >60 msec. Treatment-emergent AEs were reported in 29 of 31 patients (93.5%) in the ziprasidone group and 25 of 27 patients (92.6%) in the haloperidol group; most events were of mild or moderate severity. Frequently reported AEs were somnolence (90.3% and 81.5%, respectively), dizziness (22.6% and 7.4%), anxiety (16.1% and 7.4%), extrapyramidal symptoms (6.5% and 33.3%), agitation (6.5% and 18.5%), and insomnia (0% and 14.8%). CONCLUSIONS In this study of the effects of high-dose ziprasidone and haloperidol in patients with schizophrenic disorder, none of the patients had a QTc interval >480 msec, and changes from baseline QTc interval were clinically modest with both drugs. Both drugs were generally well tolerated.

Defining therapeutic benefit for people with schizophrenia: focus on negative symptoms.

Schizophrenia is a complex, heterogeneous, multidimensional disorder within which negative symptoms are a significant and disabling feature. Whilst there is no established treatment for these symptoms, some pharmacological and psychosocial interventions have shown promise and this is an active area of research. Despite the effort to identify effective interventions, as yet there is no broadly accepted definition of therapeutic success. This article reviews concepts of clinical relevance and reports on a consensus conference whose goal was to apply these concepts to the treatment of negative symptoms. A number of key issues were identified and discussed including: assessment of specific negative symptom domains; defining response and remission for negative symptoms; assessment of functional outcomes; measurement of outcomes within clinical trials; and the assessment of duration/persistence of a response. The group reached a definition of therapeutic success using an achieved threshold of function that persisted over time. Recommendations were agreed upon with respect to: assessment of negative symptom domains of apathy-avolition and deficit of expression symptoms; thresholds for response and remission of negative symptoms based on level of symptomatology; assessing multiple domains of function including social occupation, activities of daily living, and socialization; the need for clinical trial data to include rate of change over time and converging sources of evidence; use of clinician, patient and caregiver perspectives to assess success; and the need for establishing criteria for the persistence of therapeutic benefit. A consensus statement and associated research criteria are offered as an initial step towards developing broad agreement regarding outcomes of negative symptoms treatment.

The Management of Schizophrenia in Clinical Practice (MOSAIC) Registry: A focus on patients, caregivers, illness severity, functional status, disease burden and healthcare utilization

BACKGROUND The Management of Schizophrenia in Clinical Practice (MOSAIC), a disease-based registry of schizophrenia, was initiated in December 2012 to address important gaps in our understanding of the impact and burden of schizophrenia and to provide insight into the current status of schizophrenia care in the US. Recruitment began in December 2012 with ongoing assessment continuing through May 2014. METHODS Participants were recruited from a network of 15 centralized Patient Assessment Centers supporting proximal care sites. Broad entry criteria included patients diagnosed with schizophrenia, schizophreniform or schizoaffective disorder, presenting within the normal course of care, in usual treatment settings, aged ≥18years and able to read and speak English. RESULTS By May 2014, 550 participants (65.8% male, 59.8% White, 64.4% single, mean age 42.9years), were enrolled. The majority had a diagnosis of schizophrenia (62.0%). Mean illness duration at entry was 15.0years. Common comorbidities at entry were high lipid levels (26.9%), hypertension (23.1%) and type II diabetes (13%). Participants were categorized by baseline overall Clinical Global Impression-Schizophrenia Severity Score as minimally (9.1%), mildly (25.3%), moderately (39.9%), markedly (22.3%) and severely (3.4%) ill. Most commonly used second generation antipsychotics at entry were risperidone (17.8%), clozapine (16.5%), olanzapine (14.0%), aripiprazole (13.6%) and quetiapine (5.6%). CONCLUSIONS No large-scale patient registry has been conducted in the US to longitudinally follow patients with schizophrenia and describe symptom attributes, support network, care access and disease burden. These data provide important epidemiological, clinical and outcome insights into the burden of schizophrenia in the US.

Early improvement on antipsychotic treatment as a predictor of subsequent response in schizophrenia: analyses from ziprasidone clinical studies

We examine data from short‐term placebo‐controlled and comparator‐controlled clinical trials of ziprasidone in schizophrenia to confirm the predictive capacity of early symptom changes for response. We pose the question of how early is too early to consider “stay or switch” and evaluate the predictive capability of a clinical measure in this regard.

Clinical Global Impression of Improvement (CGI-I) as a valid proxy measure for remission in schizophrenia: Analyses of ziprasidone clinical study data

OBJECTIVE To determine the degree to which a proxy measure of remission in schizophrenia correlates with the criteria identified by the Remission in Schizophrenia Working Group, and how well early treatment response to ziprasidone predicts remission. METHODS Data from 10 ziprasidone studies were analyzed to determine rates of remission achieved with ziprasidone using a remission definition of Clinical Global Impression of Improvement (CGI-I) of 1, and compared with rates of remission achieved using the remission working group criteria. Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) scores were then investigated as predictors of remission. RESULTS A CGI-I score of 1 correlated with the remission criteria developed by the remission working group. In the combined ziprasidone arms, BPRS scores at Weeks 1, 3, and 4 successfully predicted PANSS remission (p<0.01) and BPRS remission (p<0.0001) at study endpoint (44-196weeks). PANSS scores (at Weeks 1, 3, and 4) successfully predicted PANSS remission (p<0.01) at study endpoint. PANSS scores at Week 3 successfully predicted BPRS remission (p=0.02) at study endpoint. A CGI-I score of 1 or 2 at Week 1 also successfully predicted remission in schizophrenia. CONCLUSION The findings show a correlation between clinical and research scales (remission working group criteria) for the assessment of remission in schizophrenia. This proxy measure for the assessment of remission should be easy to apply in a clinical setting and facilitates the prediction of remission in schizophrenia.

Examining the reliability and validity of the Clinical Assessment Interview for Negative Symptoms within the Management of Schizophrenia in Clinical Practice (MOSAIC) multisite national study

The current study sought to expand on prior reports of the validity and reliability of the CAINS (CAINS) by examining its performance across diverse non-academic clinical settings as employed by raters not affiliated with the scales developers and across a longer test-retest follow-up period. The properties of the CAINS were examined within the Management of Schizophrenia in Clinical Practice (MOSAIC) schizophrenia registry. A total of 501 participants with a schizophrenia spectrum diagnosis who were receiving usual care were recruited across 15 national Patient Assessment Centers and evaluated with the CAINS, other negative symptom measures, and assessments of functioning, quality of life and cognition. Temporal stability of negative symptoms was assessed across a 3-month follow-up. Results replicated the two-factor structure of the CAINS reflecting Motivation and Pleasure and expression symptoms. The CAINS scales exhibited high internal consistency and temporal stability. Convergent validity was supported by significant correlations between the CAINS subscales with other negative symptom measures. Additionally, the CAINS was significantly correlated with functioning and quality of life. Discriminant validity was demonstrated by small to moderate associations between the CAINS and positive symptoms, depression, and cognition (and these associations were comparable to those found with other negative symptom scales). Findings suggest that the CAINS is a reliable and valid tool for measuring negative symptoms in schizophrenia across diverse clinical samples and settings.

Characterizing relapse prevention in bipolar disorder with adjunctive ziprasidone: Clinical and methodological implications

BACKGROUND Ziprasidone, adjunctive to either lithium or valproate, has previously been shown to be associated with a significantly lower risk of relapse in bipolar disorder compared with lithium or valproate treatment alone. METHODS This placebo-controlled outpatient trial with ziprasidone adjunctive to lithium or valproate or lithium and valproate alone, for subjects with a recent or current manic or mixed episode of bipolar I disorder, comprised a 2.5- to 4-month, open-label stabilization period, followed by a 6-month, double-blind maintenance period. These post hoc analyses characterize the relapse outcomes by dose, relapse types and timing as well as all-reason discontinuations during the maintenance period. RESULTS Time to relapse and all-reason discontinuation were both statistically significant in favor of the ziprasidone 120mg/day group compared with placebo (p=0.004 and 0.001, respectively) during the 6-month double-blind period. There was no difference in time to relapse in the 80 and 160mg/day dose groups compared with placebo (p=0.16 and 0.40, respectively) and, likewise, for time to all-reason discontinuation (p=0.20 for both doses). The majority of relapses in each group occurred prior to week 8, and most were depressive in nature. LIMITATIONS The primary study was not designed to compare relapse rates by dose groups. CONCLUSIONS These analyses confirm the effectiveness of ziprasidone (80-160mg/day) in preventing relapses in subjects with bipolar disorder, with the 120mg/day dosage appearing to have the highest relapse prevention rate.