What Is the Minimum Clinically Important Change in Negative Symptoms of Schizophrenia? PANSS Based Post-hoc Analyses of a Phase III Clinical Trial (original) (raw)
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European Psychiatry, 2019
Background:Negative symptoms in schizophrenia are heterogeneous and multidimensional; effective treatments are lacking. Cariprazine, a dopamine D3-preferring D3/D2receptor partial agonist and serotonin 5-HT1Areceptor partial agonist, was significantly more effective than risperidone in treating negative symptoms in a prospectively designed trial in patients with schizophrenia and persistent, predominant negative symptoms.Methods:Using post hoc analyses, we evaluated change from baseline at week 26 in individual items of the Positive and Negative Syndrome Scale (PANSS) and PANSS-derived factor models using a mixed-effects model for repeated measures (MMRM) in the intent-to-treat (ITT) population (cariprazine = 227; risperidone = 227).Results:Change from baseline was significantly different in favor of cariprazine versus risperidone on PANSS items N1-N5 (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking) (P<.05)...
Neuropsychopharmacology, 2019
Understanding how rating scale improvement corresponds to a clinical impression in patients with negative symptoms of schizophrenia may help define the clinical relevance of change in this patient population. We conducted post hoc equipercentile linking analyses of Positive and Negative Syndrome Scale (PANSS) outcomes (e.g., PANSS-Factor Score for Negative Symptoms [FSNS]) with Clinical Global Impressions-Improvement (CGI-I) and-Severity (CGI-S) ratings on data from patients treated with cariprazine (n = 227) or risperidone (n = 229) in a clinical study evaluating negative symptoms in schizophrenia. Patients were prospectively selected for persistent, predominant negative symptoms of schizophrenia (PNS), and minimal positive/depressive/ extrapyramidal symptoms. Linking results demonstrated that greater improvement on PANSS-derived measures corresponded to clinical impressions of greater improvement, as measured by the CGI-I, and less severe disease states, as measured by the CGI-S. For example, CGI-S scores of 1 (normal), 2, 3, 4, 5, and 6 (severely ill) corresponded to PANSS-FSNS scores of 7, 13, 19, 24, 29, and 35, respectively. Likewise, CGI-I scores of minimally improved, much improved, and very much improved corresponded to a change from baseline in PANSS-FSNS scores of −27%, −49%, and −100%, respectively. These are important findings for the interpretation of the results of trials in patients with persistent negative symptoms.
Lancet (London, England), 2017
Although predominant negative symptoms of schizophrenia can be severe enough to cause persistent impairment, effective treatment options are lacking. We aimed to assess the new generation antipsychotic cariprazine in adult patients with predominant negative symptoms. In this randomised, double-blind, phase 3b trial, we enrolled adults aged 18-65 years with long-term (>2 year), stable schizophrenia and predominant negative symptoms (>6 months) at 66 study centres (mainly hospitals and university clinics, with a small number of private practices) in 11 European countries. Patients were randomly assigned (1:1) by an interactive web response system to 26 weeks of monotherapy with fixed-dose oral cariprazine (3 mg, 4·5 mg [target dose], or 6 mg per day) or risperidone (3 mg, 4 mg [target dose], or 6 mg per day); previous medication was discontinued over 2 weeks. The primary outcome was change from baseline to week 26 or end of treatment on the Positive and Negative Syndrome Scale f...
European Psychiatry
IntroductionThere is an increasing need to understand the effectiveness of novel medications in real-world context since despite being the gold standard, double-blind trials have their own limitations as well. Clinical Global Impression is a simple tool for clinicians to assess the severity of an illness (CGI-Severity) as well as to rate how much the patient’s disorder has improved or worsened relative to baseline (CGI-Improvement). In this poster, cariprazine, a third-generation antipsychotic medication that was found to be effective in the treatment of negative symptoms in schizophrenia will be evaluated.ObjectivesTo compare the effectiveness of cariprazine in clinical trial vs real-world setting via the CGI-S and CGI-I scales in negative symptom schizophrenia patients.MethodsWe compared the results of a clinical trial (Németh et al. Lancet 2017; 389:1103-13) and an observational study (Rancans et al. Int Clin Psychopharmacol. 2021;36(3):154-161). The latter was an open-label, fle...
Psychiatry Research, 2014
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 ¼0.93). 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 ¼0.71) 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 ( À 0.39) and for change at Week eight good ( À 0.65). NSFS responders (Z 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.
International journal of methods in psychiatric research, 2015
Significant changes of schizophrenia patients during inpatient treatment were evalutaed and compared to established outcome criteria. The concept of reliable and clinically significant change methods was applied to three hundred and ninety-six patients suffering from a schizophrenia spectrum disorder. First, information on whether or not the change of the patient's condition is sufficient in order to declare that it is beyond a measurement error or random effect (= reliable change) was evaluated and in a second step it was observed if the reliable change was clinically meaningful (= clinically significant change). Different Positive and Negative Syndrome Scale for Schizophrenia (PANSS) thresholds were applied to define the clinically significant change (40, 45 and 50 points). These changes were then compared to established outcome criteria such as response and remission. Seventy-nine of the 396 patients (20%) showed a reliable improvement of symptoms, whereas 70% improved withou...
European Psychiatry, 2021
IntroductionMotivation deficit is a significant aspect of lack of improvement in patients with schizophrenia especially with predominant negative symptoms (PNS). Therefore, improvement depends not only on symptoms reduction and better social functioning but also on patient engagement which is a key but less investigated aspect of successful treatment.ObjectivesTo investigate and compare patient engagement in PNS patients after cariprazine and risperidone treatment characterized by the 11 items of the Positive and Negative Syndrome Scale (PANSS-11).MethodsIn this phase 3 study patients suffering from PNS of schizophrenia (PANSS-FSNS≥24) were randomized to 26 weeks of treatment with either cariprazine or risperidone (target dose 4.5 and 4 mg/day, respectively). To compare the effects of the two drugs on patient engagement the PANSS-11 scale was used. Change from baseline (CfB) on the selected items and PANSS-11 total score were analyzed using mixed model of repeated measures approach ...
Journal of comparative effectiveness research, 2017
Our study aimed at estimating differences in quality-adjusted life year (QALY) gain for patients with predominant negative symptoms of schizophrenia treated with cariprazine compared with risperidone. A Markov model was built, based on the Mohr-Lenert approach and data derived from clinical trials, to estimate potential QALY gains of patients. Patients had higher probability of reaching better health states treated with cariprazine compared with risperidone. In the model, this resulted in an estimated QALY gain of 0.029 per patient, after 1 year of treatment. Cariprazine, which showed clinically meaningful improvement in the symptoms, and personal and social performance, can also provide significant QALY gain in the treatment of patients with predominant negative symptoms of schizophrenia compared with risperidone.
Issues and perspectives in designing clinical trials for negative symptoms in schizophrenia
Schizophrenia Research, 2013
A number of pharmacological agents for treating negative symptoms in schizophrenia are currently in development. Unresolved questions regarding the design of clinical trials in this area were discussed at an international meeting in Florence, Italy in April 2012. Participants included representatives from academia, the pharmaceutical industry, and the European Medicines Agency (EMA). Prior to the meeting, participants submitted key questions for debate and discussion. Responses to the questions guided the discussion during the meeting. The group reached agreement on a number of issues: (1) study subjects should be under the age of 65; (2) subjects should be excluded for symptoms of depression that do not overlap with negative symptoms;