Dragana Bugarski-Kirola

Negative symptoms have greater impact on functioning than positive symptoms in schizophrenia: analysis of CATIE data.

Increased attention has been given to treatment of negative symptoms and its potential impact on functional outcomes, however previous inferences have been confounded by the fact that measures of functional outcomes often use items similar to those of negative symptoms. We attempted to discern the relative effects of negative symptoms on functioning, as compared to other symptoms, using data from the National Institute of Mental Health CATIE trial of chronic schizophrenia (n=1447) by examining correlations of Positive and Negative Syndrome Scale factors, Calgary Depression Rating Scale and select items from Heinrichs and Lehmans Quality of Life Scales measuring aspects of functioning that did not overlap with negative symptoms. Baseline functioning and change in functioning were more strongly related to PANSS negative factor than any of the other symptoms - though the amount of variance explained by symptom changes in general was small. The data suggests that improvement in negative symptoms may have a distinctive and independent effect on functional outcome relative to other symptoms. This should be further tested in studies where negative symptoms improve without concomitant improvement of other symptoms.

A phase II/III trial of bitopertin monotherapy compared with placebo in patients with an acute exacerbation of schizophrenia – Results from the CandleLyte study

Bitopertin is a glycine reuptake inhibitor postulated to improve N-methyl-d-aspartate receptor hypofunction by increasing synaptic glycine concentrations. This randomised, double-blind, placebo- and active-controlled phase II/III trial evaluated the efficacy and safety of bitopertin monotherapy over 4 weeks in patients with acute exacerbation of schizophrenia. Of 301 patients randomised, 299 received placebo (n=80), bitopertin 10mg (n=80) or 30mg (n=77), or olanzapine 15mg (n=62). The primary endpoint, change from baseline in mean Positive and Negative Syndrome Scale (PANSS) total score, showed non-statistically significant improvements with bitopertin 30mg and olanzapine vs. placebo: bitopertin 10mg (-11.7; standard error [SE], 1.89; p=0.945), bitopertin 30mg (-15.3; SE, 1.87; p=0.211), olanzapine (-14.9; SE, 2.13; p=0.295) and placebo (-11.9; SE, 1.90). The PANSS positive subscale score, a secondary endpoint, also showed improvement with bitopertin 30mg (p=0.030) whereas a trend was observed with olanzapine (p=0.072) vs. placebo. Although not statistically significant, bitopertin 30mg and olanzapine reduced overall illness severity (Clinical Global Impression-Severity Scale; p=0.098 and p=0.126, respectively). More patients receiving bitopertin 30mg (51.3%) or olanzapine (52.5%) than placebo (32.9%) were ready for hospital discharge at Week 4 (bitopertin, p=0.014; olanzapine, p=0.024). In summary, this study failed due to lack of statistical separation of either bitopertin or olanzapine (active control) from placebo on the primary endpoint. Of interest, improved positive symptoms and readiness for hospital discharge were associated with both bitopertin and olanzapine treatment. Bitopertin was safe and well tolerated in this study.

Association of prominent positive and prominent negative symptoms and functional health, well-being, healthcare-related quality of life and family burden: A CATIE analysis

BACKGROUND There is an increased interest in evaluating the impact of core symptoms of schizophrenia, both positive and negative, on functioning and burden of disease. OBJECTIVE To examine the extent to which prominent positive and prominent negative symptoms impact functional health, well-being, health-related quality of life (HRQoL), and family burden. METHODS Data on symptomatology, HRQoL, and resource use from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) were analyzed (n=1447). Patients were divided into four groups based on the Positive and Negative Syndrome Scale (PANSS) using published criteria as having (a) neither prominent positive nor prominent negative symptoms (n=575; 39.7%); (b) only prominent negative symptoms (n=274; 18.9%); (c) only prominent positive symptoms (n=295; 20.4%); or (d) both prominent positive and negative symptoms (n=303; 20.9%). Differences were examined for overall significance between the groups and for a linear trend. RESULTS There was a significant linear decline in the outcome measures with each subsequent symptom group, with the combination of prominent positive and negative symptoms incrementing the decline further on quality-adjusted life-years derived from the PANSS, Short-Form-12, Index of Functioning, HRQoL measures, and number of workdays missed by caregiver during the month prior to CATIE (all p<0.001). CONCLUSIONS Both prominent positive and prominent negative symptoms of schizophrenia are independently associated with significant decline in functionality, HRQoL, and caregiver lost workdays. An increased burden is observed in patients with highest symptomatology. Further research is needed to determine predictors of poor outcomes and burden of schizophrenia.

Report on ISCTM Consensus Meeting on Clinical Assessment of Response to Treatment of Cognitive Impairment in Schizophrenia

If treatments for cognitive impairment are to be utilized successfully, clinicians must be able to determine whether they are effective and which patients should receive them. In order to develop consensus on these issues, the International Society for CNS Clinical Trials and Methodology (ISCTM) held a meeting of experts on March 20, 2014, in Washington, DC. Consensus was reached on several important issues. Cognitive impairment and functional disability were viewed as equally important treatment targets. The group supported the notion that sufficient data are not available to exclude patients from available treatments on the basis of age, severity of cognitive impairment, severity of positive symptoms, or the potential to benefit functionally from treatment. The group reached consensus that cognitive remediation is likely to provide substantial benefits in combination with procognitive medications, although a substantial minority believed that medications can be administered without nonpharmacological therapy. There was little consensus on the best methods for assessing cognitive change in clinical practice. Some participants supported the view that performance-based measures are essential for measurement of cognitive change; others pointed to their cost and time requirements as evidence of impracticality. Interview-based measures of cognitive and functional change were viewed as more practical, but lacking validity without informant involvement or frequent contact from clinicians. The lack of consensus on assessment methods was viewed as attributable to differences in experience and education among key stakeholders and significant gaps in available empirical data. Research on the reliability, validity, sensitivity, and practicality of competing methods will facilitate consensus.

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.

Reliability, validity and ability to detect change of the PANSS negative symptom factor score in outpatients with schizophrenia on select antipsychotics and with prominent negative or disorganized thought symptoms

The PANSS is a valid instrument assessing schizophrenia symptom severity. Analyses have identified a five-factor solution. The negative symptom factor (NSFS) is robust, having been replicated in multiple analyses. The score has superior content validity versus the negative subscale. Aspects of validity in patients with predominant negative symptoms have yet to be established. The present data are from a Phase IIb study of add-on bitopertin therapy in schizophrenia outpatients with prominent negative or disorganized thought symptoms treated with antipsychotics. Analyses were conducted to evaluate reliability, validity and sensitivity to change. Test-retest screening to baseline was high (ICC=0.93). This was maintained in-study, for patients with no change in CGI negative symptom severity (CGI-S-N). Internal consistency at baseline was adequate (α=0.71) and increased at later assessments. Pearson correlation at baseline showed a good association between NSFS and CGI-S-N (0.63), but not overall CGI-S (0.31). Association with PSP at baseline was moderate (-0.39) and for change at Week eight good (-0.65). NSFS responders (≥20% improvement) at Week eight showed a significant improvement in function. The analyses demonstrated reliability, validity and ability to detect change of the NSFS, in schizophrenia patients with prominent negative or disorganized thought symptoms.

EFFICACY AND SAFETY OF ADJUNCTIVE BITOPERTIN VERSUS PLACEBO IN SUBJECTS WITH PERSISTENT PREDOMINANT NEGATIVE SYMPTOMS OF SCHIZOPHRENIA TREATED WITH ANTIPSYCHOTICS – UPDATE FROM THE SEARCHLYTE PROGRAMME

Results: Young people living with psychosis had high rates of most WHOdefined risk factors for death and disability. Their rates of tobacco use were more than double the general population, and virtually all were sedentary or had very low rates of physical activity. Most did not eat daily recommended amounts of fruit and vegetables. Obesity was common, and comparison with the AusDiab sample showed that the psychosis population had higher rates of obesity even from the age of 25 years. In addition, from age 25 years, people with psychosis had significantly higher diastolic blood pressure, triglycerides and glucose (in women), and lower HDL-cholesterol. There were gender differences, for example tobacco use was more common in young men whilst young women were more likely to meet criteria for at-risk waist circumference. Conclusions: Many of the risk factors for premature death are present from a young age in people with psychosis. It is therefore likely that people with these disorders will continue to experience poor physical health and premature mortality, unless measures are put in place to address these risk factors. Such measures need to be an integral component of early intervention services for young people with psychotic disorders, and to continue to be provided as an essential part of comprehensive mental health care across the lifespan.

Psychometric evaluation of the Work Readiness Questionnaire in schizophrenia

Objective/Introduction Unemployment can negatively impact quality of life among patients with schizophrenia. Employment status depends on ability, opportunity, education, and cultural influences. A clinician-rated scale of work readiness, independent of current work status, can be a valuable assessment tool. A series of studies were conducted to create and validate a Work Readiness Questionnaire (WoRQ) for clinicians to assess patient ability to engage in socially useful activity, independent of work availability. Methods Content validity, test–retest and inter-rater reliability, and construct validity were evaluated in three separate studies. Results Content validity was supported. Cronbach’s α was 0.91, in the excellent range. Clinicians endorsed WoRQ concepts, including treatment adherence, physical appearance, social competence, and symptom control. The final readiness decision showed good test–retest reliability and moderate inter-rater reliability. Work readiness was associated with higher function and lower levels of negative symptoms. Low positive and high negative predictive values confirmed the concept validity. Discussion The WoRQ has suitable psychometric properties for use in a clinical trial for patients with a broad range of symptom severity. The scale may be applicable to assess therapeutic interventions. It is not intended to assess eligibility for supported work interventions. Conclusions The WoRQ is suitable for use in schizophrenia clinical trials to assess patient work functional potential.

Validity and utility of the PANSS negative symptoms factor score as a clinical trial outcome

Validity and utility of the PANSS negative symptoms factor score as a clinical trial outcome☆ Chris J. Edgar , Thomas Blaettler , Dragana Bugarski-Kirola , Stephanie Le Scouiller , George M. Garibaldi , Stephen R. Marder d a Roche Products Ltd., United Kingdom b Department of Neuroscience, F. Hoffmann-La Roche, Switzerland c F. Hoffmann-La Roche, Switzerland d Desert Pacific Mental Illness Research, Education, and Clinical Center, Semel Institute for Neuroscience at UCLA, United States