The NIMH-MATRICS consensus statement on negative symptoms is an excellent article. I think that this kind of consensus is needed in the field of behavioral research, and specifically in the field of schizophrenia research. We know a lot about the positive symptoms of the disease, but the weakest points of research in schizophrenia are the negative symptoms and the cognitive impairments of the pathology. This need for consensus is necessary not only at a clinical level, but also at a behavioral research level.

Thus, this consensus must be developed, and it will be a point of more discussion. The psychopharmacology is one of the most outstanding aspects of the discussion. At a first look, the psychopharmacology has failed by focusing its attention on reducing positive symptoms. In the discrimination of negative symptoms, sometimes it is difficult to separate primary from secondary negative symptoms, and I think that this distinction is needed. I think that a consensus about negative symptoms has just started and a lot of work is needed.

References:

Kirkpatrick B, Fenton WS, Carpenter WT Jr, Marder SR. The NIMH-MATRICS Consensus Statement on Negative Symptoms. Schizophr Bull. 2006 Apr;32(2):214-9. Epub 2006 Feb 15. No abstract available. Abstract

View all comments by Patricia Estani

The development of a consensus statement on the treatment of negative symptoms in schizophrenia is an extremely positive development. Negative symptoms represent a fundamental feature of schizophrenia and have been very poorly treated in the past. While I was a member of the consensus panel and contributed a paper to the special issue, I was not an author of the consensus statement. Thus, I am commenting on the strengths of the consensus statements and on some of the intrinsic challenges of treatment development for negative symptoms.

Strengths
This consensus statement clearly attempts to delineate between negative symptoms and other features of the illness. While negative symptoms were historically delineated quite clearly from positive symptoms, various definitions of negative symptoms manifested considerable overlap with other features of the illness such as cognitive symptoms and deficits in the performance of everyday living skills. Such a delineation is critical, because it is clear that impairments in performance on cognitive tests are not markedly...  Read more

The development of a consensus statement on the treatment of negative symptoms in schizophrenia is an extremely positive development. Negative symptoms represent a fundamental feature of schizophrenia and have been very poorly treated in the past. While I was a member of the consensus panel and contributed a paper to the special issue, I was not an author of the consensus statement. Thus, I am commenting on the strengths of the consensus statements and on some of the intrinsic challenges of treatment development for negative symptoms.

Strengths
This consensus statement clearly attempts to delineate between negative symptoms and other features of the illness. While negative symptoms were historically delineated quite clearly from positive symptoms, various definitions of negative symptoms manifested considerable overlap with other features of the illness such as cognitive symptoms and deficits in the performance of everyday living skills. Such a delineation is critical, because it is clear that impairments in performance on cognitive tests are not markedly overlapping with negative symptoms, and it is also clear that impairments in everyday living skills are multiply determined. Given the multiplicity of factors that determine everyday living impairments (cognitive deficits, opportunities, societal factors, and motivation, among others), it is hard to imagine a single treatment that would target negative symptoms as they have been broadly defined in the past.

Further, the statement specifies a trial design that is practical and sensible. The statement clearly delineates between what we know (that treatments that affect multiple clinical dimensions are not likely to receive an FDA indication) and what we do not know (what is the effect size for treatment change that is meaningful). Much like the problems confronting the TURNS project (following from the MATRICS initiative), we are in the situation of trying to identify measures that are sensitive to change in a set of symptoms where there has been little treatment-related change detected in the past. Thus, the reasons for failures of previous treatment efforts cannot be disentangled; we do not know if poor outcomes have been due to poor treatments or insensitive outcomes measures.

Challenges
The challenges in this endeavor are many.

Animal models for negative symptoms are more difficult to develop than for cognitive symptoms, in that many negative symptoms are defined in terms of intrinsically human attributes (hedonic capacity, affective range, verbal output). Thus, the first steps in targeting for drug development are hard to specify.

Selection of samples may be problematic, because for many patients their negative symptoms do not pose a basis for complaint or a treatment target. Finding the target population may be challenging, particularly for people with schizophrenia who have minimal current psychotic symptoms. Further, the prevalence of negative symptoms is probably lower, particularly in terms of persistent symptoms unaccompanied by psychosis, than that of cognitive impairment. As a result, subjects will have to meet entry criteria for the studies, and development of the entry criteria will likely be an iterative process leading to higher risk of failures for early trials than later ones.

There is also a distinct lack of information available on the potential neuropharmacological targets for negative symptoms treatment. In contrast to the substrates of cognitive impairments, where there are multiple transmitter systems implicated (glutamate, dopamine, serotonin, norepinephrine, acetylcholine), there is little similar information available regarding the substrates of negative symptoms. Similar to previous efforts like the CONSIST study, it is likely that phase 2 development programs will look at both cognitive and negative symptoms, evaluate the differential response of these two domains, and aim the development program at the stronger signal. While this may be the only available approach, it also increases the risks of failure at phase 3, because of the lack of strong differential rationale for the treatments.

Conclusion
Targeting negative symptoms is an important treatment goal, and this consensus statement brings clarity to the effort. Assessment scales to be developed under the auspices of this initiative may also facilitate this effort as well. While the challenges are substantial, having a method that is promising is likely to spur development efforts. At this point, it will remain to be seen whether current and future pharmacological approaches can improve or eliminate negative symptoms.

Phil Harvey's comments are excellent. I do not share his pessimism for animal models of negative symptoms, however. Models of anhedonia were developed years ago by Roy Wise—worrisomely, a neuroleptic induced model (Wise et al., 1978). Social drive/affiliation can be modeled. Motivation models may be relevant, and animal models of empathy may also be of interest.

View all comments by William Carpenter

The consensus statement for the treatment of negative symptoms in schizophrenia is excellent. In a recent study, quantitative proton magnetic resonance spectroscopy was used to measure metabolic changes in the frontal lobe (Tanaka et al., 2006). A reduction of N-acetylaspartate in the left frontal lobe was shown to be related to negative symptoms and card sorting cognitive dysfunction in schizophrenia. The implication of this finding is that one might treat the negative symptoms by using tasks which stimulate the left frontal lobe and N-acetylaspartate.

References:

Tanaka Y, Obata T, Sassa T, Yoshitome E, Asai Y, Ikehira H, Suhara T, Okubo Y, Nishikawa T. Quantitative magnetic resonance spectroscopy of schizophrenia: Relationship between decreased N-acetylaspartate and frontal lobe dysfunction. Psychiatry and Clinical Neurosciences. 2006;60(3):365-372.

View all comments by Kiumars Lalezarzadeh