Co-chairs: Stephen Marder, MD; David Daniel, MD
Dr. Marder reviewed all the studies of negative symptoms posted on clinicaltrials.gov. All the trials were studying add-on treatment. A study by Amgen of a GlyT1 compound, AMG747, was new. The duration of the study is 12 weeks, not as long as the studies being conducted by Roche. The studies generally include ages 18 to 55, 60, or 65. Many studies are using the SANS as the scale for primary outcome measure. Roche is using the PANSS negative factors and Amgen and Lilly are using the NSA-16. Almost all trials require limitation on severity of positive symptoms.
The group reviewed a summary of the recommendations that resulted from the NewMeds meeting in Florence in April 2012. Several issues had been agreed upon prior to the meeting and others were agreed to at the meeting. Among the recommendations agreed upon were:
- Subjects entered into negative symptom trials should have no fewer than two negative symptoms and at least one should be rated as moderate or greater.
- Ratings for negative symptoms should include a single global score.
- Ratings for negative symptoms should include global scores for major domains such as expressiveness and apathy/asociality.
- Subjects currently treated with clozapine should not be excluded in negative symptom trials of co-medication.
- Patients in proof-of-concept studies should be under the age of 65.
- Patients should be excluded for the presence of depressive symptoms that do not overlap with negative symptoms. Patients with a co- diagnosis of MDD should be excluded.
- Functional measures should not be required as co-primary endpoints but they should be key secondary measures.
Some of the issues agreed to at the NewMeds meeting were discussed and debated. Should the population be one where negative symptoms predominate? Should global measures be used? Are apathy and asociality the symptoms most sensitive to drug effects? It was suggested on the last point that the answer to the last question will depend on the mechanism of action of the drug. Avolition, apathy, and amotivation responded best and correlated well with function.
There was agreement that items measuring negative symptoms have function embedded within them. Functional endpoints are useful if the clinical relevance of an endpoint is not understood. Both the NSA and the PANSS were thought to correlate well with functional outcomes.
The question of whether we are targeting a subset of patients with predominant negative symptoms or whether these symptoms were symptoms of schizophrenia in general was discussed at length. While there was not full agreement, the majority seemed to believe that the is a distinct subset of patients with predominant negative symptoms and these patients, and not patients with simply prominent negative symptoms should be the population studied, at least in phase 2 studies.
Future Plans: 1) Address the following unresolved issues: a) Subject selection with respect to predominant vs. prominent negative symptoms and age; b) most appropriate indicators of clinical stability; c) best tools for interview based and objective negative symptoms assessment ; d) selection of functional capacity and real world functioning tools for negative symptoms trials; differentiation of depressive and negative symptoms. 2) Monitor results of ongoing clinical trials as they impact methodological issues and potentially publish an update to the working group’s previous publication in Schizophrenia Bulletin.