Negative symptoms in schizophrenia – the remarkable impact of inclusion definitions in clinical trials and their consequences
Section snippets
Methods
All criteria were based on the Positive and Negative Syndrome Scale (PANSS). Prominent negative symptoms were operationally defined as (1) Baseline score ≥ 4 (moderate) on at least 3, or ≥ 5 (moderately severe) on at least 2 negative PANSS subscale items (Kinon et al., 2006, Stauffer et al., 2012); or (2) PANSS negative subscale: score > 3 on item 1 (blunted affect) and item 6 (lack of spontaneity and flow of conversation) and at least one third item with a score > 3 and a maximum of two items with a
Data
The NewMeds repository consists of data from 29 placebo controlled RCT's of second generation antipsychotics (placebo, n = 2200, study drug and active control, n = 6971), nine studies were excluded from the present analysis as PANSS item level data was not available (placebo, n = 1673, drug, n = 5721). The repository includes anonymized patient data from AstraZeneca, Janssen Pharmaceuticals, Eli Lilly, Lundbeck, and Pfizer from placebo-controlled positive trials of SGA's approved for treating
The impact of definition on acute patients
At baseline, of the patients in these studies, 8.1% and 62.3% met criteria for either of the two definitions for prominent negative symptoms and 10.2% to 50.2% met criteria for the four definitions of predominant negative symptoms (Table 1). EMA criteria for selecting patients with predominant negative symptoms for clinical trials were met by 7.6% to 33.78% of patients. After 6 weeks of active treatment, 12.2% to 26.7% of patients met EMA criteria based on the various published definitions of
Discussion
We attempted to examine the utility of various definitions of negative symptoms for selecting patients with negative symptoms in schizophrenia trials. In a schizophrenia population, as conventionally included in efficacy studies for SGAs (often in acute exacerbation), applying the various operational criteria for prominent or predominant negative symptoms at baseline leads to a large range of percentages of patients fulfilling these criteria. Based on EMA criteria for selecting patients with
Role of funding source
This work was supported from the Innovative Medicine Initiative Joint Undertaking under grant agreement n° 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013). Funding source had no editorial role.
Contributors
Jonathan Rabinowitz drafted the manuscript and analyzed the data.
Nomi Werbeloff analyzed the data and prepared tables. Ivo Caers, Francine S. Mandel, Virginia Stauffer, François Menard, Bruce J. Kinon and Shitij Kapur were involved in conceptualizing the study, developing the study plan and interpreting the results. All author's reviewed and commented on multiple versions of the manuscript and approved the final version.
Conflict of interest
Dr. Rabinowitz has received research support, and/or consultancy fees and/or travel support from Janssen (J&J), Eli Lilly, Pfizer, BiolineRx, F. Hoffmann-La Roche, Amgen, Avraham Pharmaceuticals and Newron Pharmaceuticals. Nomi Werbeloff has no conflict of interests to report. Ivo Caers is an employee of Johnson & Johnson and a stock holder in that company. Francine S. Mandel is an employee of Pfizer. Bruce J. Kinon and Virginia Stauffer are employees of Eli Lilly and Company and a stockholders
Acknowledgment
The research leading to these results has received support from the Innovative Medicine Initiative Joint Undertaking under grant agreement n° 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013). Funding source was not involved in the collection, analysis, and interpretation of data; in the writing of the report; and nor in the decision to submit the paper for publication.
References (13)
- et al.
Differential relationships between positive and negative symptoms and neuropsychological deficits in schizophrenia
Schizophr. Res.
(1997) - et al.
The factor structure for the Positive and Negative Syndrome Scale (PANSS) in recent-onset psychosis
Schizophr. Res.
(2003) - et al.
Negative symptoms have greater impact on functioning than positive symptoms in schizophrenia: analysis of CATIE data
Schizophr. Res.
(2012) - et al.
Responses to antipsychotic therapy among patients with schizophrenia or schizoaffective disorder and either predominant or prominent negative symptoms
Schizophr. Res.
(2012) - et al.
The timing of negative symptom exacerbations in relationship to positive symptom exacerbations in the early course of schizophrenia
Schizophr. Res.
(2004) Guideline on clinical investigation of medicinal products, including depot preparations in the treatment of schizophrenia
Cited by (60)
Social interaction, psychotic disorders and inflammation: A triangle of interest
2023, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Additionally, it was discussed that stress could contribute to symptom severity (Lee and Schepp, 2009). Further, the problem of exact inclusion definitions of negative symptoms in clinical trials was discussed (Rabinowitz et al., 2013). Social isolation is objective; loneliness is subjective (Wang et al., 2017).
Increasing social and community participation in veterans living with schizophrenia: A treatment outcome study
2023, Schizophrenia ResearchDivergent relationship between brain structure and cognitive functioning in patients with prominent negative symptomatology
2021, Psychiatry Research - NeuroimagingTreating negative symptoms of schizophrenia: Current approaches and future perspectives
2023, British Journal of Psychiatry