Developing Treatments for Schizophrenia in the 21st Century: Preventing Disease Progression—A Novel Paradigm for Research

Chairs:  Ravi Anand, MD; George Haig, PharmD, MBA; Larry Alphs, MD, PhD

Since the revolutionary introduction of antipsychotic medication over 60 years ago, little progress has been made in the treatment of schizophrenia.  Research since that time has largely focused on the acute and long-term management of positive symptoms and on improving the safety profile of medications.  Additional progress towards improving quality of life, functioning, and long-term outcome of persons with schizophrenia that was anticipated in the years immediately following the discovery of antipsychotic treatments has not been realized.  Instead, recidivism, hospitalization, incarceration and suicide rates remain high, and overall quality of life remains unsatisfactory.

In particular, little effort has been devoted to understanding the progression of schizophrenia. The disease follows a relatively benign course in some patients, while there is a significant deterioration in all aspects of behavior, functioning and quality of life in many  patients. It is unclear if the disease is characterized by brain changes over time that account for the worsening of symptoms, or the changes that appear later reflect the consequence of the initial insult.  Indeed, we have little true understanding of phenomenology of its progression or the biological processes underlying it.  For example, we do not know if schizophrenia progresses uniformly across the spectrum of patients with the condition nor which, if any, of the symptom domains are reversible at any point after the onset of the disorder.  Prediction of which patients will progress is hampered by lack of phenotypic and genotypic  markers. Biological correlates of progression have not been reliably identified. The absence of this knowledge means that our ideas about what and how to target changes in disease progression are at best speculative.  Further, we are not really sure of what should be measured when trying to develop treatments that modify treatment progression. 

The new frontier in managing schizophrenia must be to arrest , or significantly attenuate the progression of the disease after the first episode. Achievement of significant breakthroughs in schizophrenia requires knowledge of how, and in whom does the disease progress, what domains does progression affect, what measures can chart the worsening, what separates the patients who progress from those who do not, and what influences the rate of progression. The answers to these and similar questions need to be addressed prior to identifying biological mechanisms that could influence modulate disease progression in schizophrenia.  Experience suggests that it is unlikely that modulation of neurotransmitters alone will achieve meaningful and long term benefits to patients, or alter the course of the disease. 

Academia, industry, and governments must work together on identifying and filling the knowledge gaps  for this endeavor to be viable. This ground-breaking session will include an international , multi-disciplinary faculty of speakers who will examine the concepts and challenges faced in developing new treatments that may modify the course of schizophrenia.  The longitudinal course of schizophrenia will be reviewed and measures that could characterize the progression of symptom domains, and/or biological markers that correlate with disease progression will be examined. In addition, we will discuss directions for identifying better disease modifying treatments as well as considerations regarding the design of clinical trials required to demonstrate disease modification. This will include discussion of the regulatory and developmental challenges associated with such treatment development.