Ernst Strüngmann Forum

 

Schizophrenia

Evolution and Synthesis

Steven M. Silverstein, Bita Moghaddam, and Til Wykes, Chairpersons

July 22–27, 2012

Program Advisory Committee

Anil Malhotra, The Zucker Hillside Hospital, Glen Oaks, NY 11004, U.S.A.
John McGrath, Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Summer Park BC, Australia
Andreas Meyer-Lindenberg, Director, Central Institute of Mental Health, Mannheim and Chairman of Psychiatry and Psychotherapy, University of Heidelberg, Germany
Bita Moghaddam, Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, U.S.A.
Steven M. Silverstein, Director, Division of Schizophrenia Research, University of Medicine and Dentistry of New Jersey, Piscataway, NJ, U.S.A.
Til Wykes, Institute of Psychiatry, King's College London, U.K.

Goal

To explore novel ways of conceptualizing the disorder, integrating data across levels of analysis, and accelerating advances in treatment development and prevention efforts.

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Justification

Schizophrenia is a diagnostic term describing a serious mental disorder that affects approximately 1% of the population worldwide, with a current global prevalence calculated at over 20 million people (McGrath et al. 2008). Common features of the illness include hallucinations, delusions, bizarre behavior, lack of interest in and/or active avoidance of socialization, and cognitive impairment. Schizophrenia is typically diagnosed in late adolescence or early adulthood, and is often associated with lifelong disability, especially when appropriate services are not provided. For example, in the United States, it has been estimated that as many as 10% of all disabled persons are diagnosed with schizophrenia (Rupp and Keith 1993). In addition, in the United States the diagnosis accounts for 75% of all mental health expenditures and approximately 40% of all publicly funded disability payments (Martin and Miller 1998). Among people with the diagnosis, 80–85% are typically unemployed at any one time, and those who do obtain a job typically work for only a few hours per week and quit, or are fired, after several weeks or months (Silverstein and Bellack 2008).

Schizophrenia is also financially costly for individuals, families, and societies. For example, in the United States alone, the cost of treating people diagnosed with schizophrenia has been estimated to be $62.7 billion (50 billion Euros) per year, including direct treatment costs and lost business productivity due to patient and family caretaker work absence (Wu et al. 2005). European studies indicate high treatment costs as well, although they are lower in southern European countries due to the fact that older, less expensive medications are primarily used and patients tend to live with families instead of in residential facilities. For example, the total cost per year, per patient, was €36,978 in Zürich and €16,868 in Mannheim, but only €2958 in Granada (Salize et al. 2009). Note that these European cost estimates represent only the direct costs of treatment; they do not include indirect costs such as lost work productivity of patients and families, or legal costs, which typically double the overall cost estimate. In short, by any standard, schizophrenia is a major individual, family, and public health problem.

Numerous advances in research technology (e.g., in molecular biology and brain imaging) and psychopharmacology have occurred in recent years. However, despite the fact that our accumulation of new findings about schizophrenia is increasing faster than ever, the general sense in the field is that we are not getting closer to an integrated understanding of the disorder or to better methods to treat it (e.g., Insel 2009). Moreover, progress has not been made on a number of critical issues. For example (see Insel 2009, 2010; Kemp et al. 2010):

  • Diagnosis is still made relatively late in the course of the neurodevelopmental trajectory.
  • Prediction of who will develop the illness is poor.
  • Etiology remains poorly understood, and prevention is not well developed.
  • We still do not know whether it is one or more disorders.
  • Treatment is by trial and error.
  • Mortality has not decreased over the past 100 years as it has for many other diseases.
  • The average life span for a person with schizophrenia averages ~25 years less than for people without the disorder and this has not changed for at least 50 years.
  • Treatment outcomes in some domains are arguably equivalent to what they were 100 years ago.
  • The effect size of the difference between active treatments and placebo has decreased.
  • Few patients are able to work or live independently.

Moreover, despite many psychopharmacological developments over the past 20 years, increased effectiveness has not been demonstrated over first-generation medications, treatment noncompliance is high (Lieberman et al. 2005), and several major pharmaceutical companies are eliminating new drug development efforts targeting psychotic disorders. Similarly, despite many psychosocial treatment developments over the past 20 years, meta-analyses of some widely used interventions indicate small or near-zero effect sizes (e.g., Lynch et al. 2010), with inverse relationships between study quality and effect size (e.g., Wykes et al. 2008).

Fifteen years ago many researchers thought that genetics would provide answers to guide treatment, in the form of a relatively small number of genetic abnormalities. It now appears, however, that the number of genome “lesions” may be over 1 million, and thus it is becoming increasingly difficult to develop and maintain an understanding of the genetic basis of schizophrenia. Moreover, many genetic findings have not been replicated, and the extent to which this is due to greater than expected human variation, illness heterogeneity, and/or false positives is not known.

Another technique that offered much promise 15 years ago, and which spawned a great deal of investment, was functional magnetic resonance imaging (fMRI). After thousands of studies, we have now demonstrated that nearly all areas of the brain can function abnormally in schizophrenia, depending on the task. However, it is becoming increasingly clear that schizophrenia is not the sum of multiple independent brain dysfunctions, but rather the result of altered connectivity between and within brain regions, and altered coordination of brain activity (Phillips and Silverstein 2003). Despite this realization, the origins of this problem, how it generates symptoms and the subjective experiences of the illness, and how to treat it are far from clear. Therefore, as with genetics, despite our increased understanding of the biological basis of schizophrenia, the gap between our knowledge base and a comprehensive grasp of the nature of the disorder and how to treat it remains large.

In addition, despite major investments in studies of cognitive impairment—a factor thought to be closer to the basis of the illness than symptoms or behaviors—it remains difficult to isolate specific deficits from generalized cognitive impairments and motivational deficits, thus limiting our ability to understand the neural basis of the abnormalities. Furthermore, behavioral studies of cognition generally have larger effect sizes than psychophysiological or neurobiological studies (Heinrichs 2001), which is the opposite of what was expected to occur with the application of techniques such as fMRI to studies of cognitive impairment in schizophrenia. Moreover, in both the behavioral and physiological domains, it is typical for an abnormal finding to be present in only 30–70% of patients, raising questions about the meaning of the deficit for the illness (Heinrichs 2001). Issues of diagnostic specificity are also often ignored, despite the fact that some of the most consistent findings from imaging studies (e.g., reduced hippocampal volumes) are also found in other populations (e.g., people who have been abused; Bremner et al. 2003), suggesting that some findings may reflect non-specific factors such as chronic stress.

Finally, unlike other disorders (e.g., coronary artery disease), where the relationship between epidemiology and pathogenesis is generally understood, in schizophrenia, research on the interaction of these factors has, for the most part, remained separate (McGrath and Richards 2009). This has seriously limited the development of comprehensive theories of the disorder that integrate societal, biological, and developmental perspectives. However, recent studies indicate important roles for factors such as cannabis use, stress, negative family environments, physical and sexual abuse, viral exposure, and racial discrimination and other forms of chronic social defeat in increasing risk for schizophrenia (e.g., González-Pinto et al. 2011; Kirkbride et al. 2008; Lysaker et al. 2007; Tienari et al. 2004; Wicks et al. 2005; Wicks et al. 2010). Therefore, frameworks that conceptualize the development of schizophrenia within a societal context need to be developed.

Progress in addressing the issues noted above requires more than just incremental additions to the existing research base. Rather, a forum is needed in which our recent advances in knowledge can be put together across levels of analysis. We envision this taking place within the context of an in-depth process wherein, in addition to multi-level integration, the assumptions behind current research and treatment paradigms, the strengths and limitations of existing methods, and the barriers to progress, are made explicit and then challenged, with the goal of developing novel perspectives, paradigms, and collaborative strategies. This rarely happens at traditional research conferences, which are data-driven and where investigators’ latest findings are presented. Moreover, at most meetings, presentations and discussions are grouped on the basis of a single method or topic (e.g., cognition, fMRI studies); integration across levels of analysis is not an explicit goal. However, we believe that multi-level integration is necessary, and that it will raise challenges to the current paradigms, thereby leading to the emergence of novel ones. This integration constitutes, therefore, one of the primary goals of the proposed forum.

An organized process to achieve these specific goals has not occurred before and we are not aware of a plan for it to occur anywhere else. To ensure the success of such an endeavor, we will invite thought leaders from all of the key areas of schizophrenia research (e.g., animal modeling, genetics, neurophysiology, psychopharmacology, imaging, cognition, phenomenology, psychosocial treatment, service delivery, public policy, environmental and societal contexts that increase/decrease risk for schizophrenia, and others) as well as regulatory experts (who can inform about matters related to medication development and approval) and foster interaction between people who normally do not interact with each other, in order to achieve maximum progress on the critical issues.

Our aim is to (a) identify those factors (e.g., paradigmatic, illness-related, institutional, financial, societal) that are preventing breakthroughs and (b) explore alternative and novel ways of conceptualizing, modeling, diagnosing, treating, and researching the disorder. Our goal is to produce a document that is not a simple addition to the research literature, but rather, a blueprint for future work that will change and improve the way schizophrenia research and treatment is carried out, thereby improving the lives of patients and their families.

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Group 1: Which aspects of heterogeneity are useful to translational success?

For many years, schizophrenia has been viewed as a single condition. However, there is no finding that is pathognomonic of schizophrenia, and the best available evidence indicates that specific abnormalities (e.g., in cognition, psychophysiology, neuroanatomy) are found in only 30–70% of patients (Heinrichs 2001). Moreover, genetic data are increasingly indicating that schizophrenia is a heterogeneous condition (Mitchell and Porteous 2011; Sebat et al. 2009). This view is consistent with recent initiatives to redefine what we now call schizophrenia in terms of basic processes (Insel et al. 2010). Therefore, this group will consider:

  • Is “schizophrenia” still a useful concept for improving outcome?
  • Are factors inherent to schizophrenia more important in determining outcome than secondary factors (e.g., factors such as IQ, personality, cultural background, comorbid psychiatric symptoms)?
  • Which dimensions of heterogeneity are most relevant for treatment outcomes and what are the implications of this for novel treatment development?
  • In what ways can findings from different levels of analysis (e.g., genetic, biological, cognitive, behavioral, phenomenological) each contribute to the development of new treatment strategies?

Group 2: How can risk and resilience factors be leveraged to optimize discovery pathways?

There is clear evidence that genetic factors play a role in the development of schizophrenia. However, the pathways from genes to phenotype are complex and not well understood. Further, there is evidence for nongenetic risk in schizophrenia. However these underlying mechanisms are also poorly understood. There is also convergent evidence for neurodevelopmental factors influencing the risk of schizophrenia, although to date, the influence of this information on treatment development has been minimal. Finally, evidence exists on environmental protective factors that may reduce the risk of the expression of schizophrenia. This group will aim to integrate data across levels of analysis and bodies of findings for the purpose of synthesizing the evidence on risk and resilience across the lifespan. Goals for this group include clarifying a research agenda for progress in risk and resilience research as it applies to schizophrenia, and exploring how available evidence can inform treatment development.

  • In what ways do genetic factors increase risk for schizophrenia, in what ways can this information inform treatment development, and what can be done to accelerate this process?
  • What are the effects of familial, societal, cultural, and environmental contexts on the development, expression, and course of schizophrenia?
  • Can we identify critical periods of brain development (prenatal, childhood, adolescence, post-illness onset, old age) to leverage intervention development?
  • How should resilience factors be incorporated in existing or new treatments?

Group 3: How can models be better utilized to enhance outcome?

Much research on schizophrenia, especially on neurophysiology and drug development, is done with rodents and, to a lesser extent, non-human primates. Indeed, as in other medical conditions, research on basic neurophysiology and drug development has required, and benefitted from, decades of research on animals. However, schizophrenia has a number of features that are distinctly human. Group 3 will discuss the value and shortcomings of cellular, animal, and network models for furthering our understanding of, and ability to treat, the disorder.

  • How can nongenetic aspects of schizophrenia be modeled?
  • How do nonanimal models complement and contrast with animal models?
  • In there a distinction between animal models of etiology versus animal models for identifying treatment targets?
  • How can we develop models to address aspects of the illness other than the traditional areas of cognition and symptoms (e.g., cellular and network disruptions)?
  • How can we develop and take advantage of human models to facilitate treatment development?
  • If core features of the disorder cannot be modeled in animals (e.g., thought disorder, self-disturbance), what are the implications for driving the research agenda?

Group 4: What is necessary to enhance development and utilization of treatment?

Over the past 100 years, major developments have occurred in psychopharmacology and psychosocial treatment for people with schizophrenia. However, it has been argued (Insel 2009) that outcomes have not improved significantly. Relatedly, compliance with medications is poor (e.g., 74% of patients discontinue medication within 18 months; Lieberman et al. 2005), and only a small percentage of patients receive evidence-based psychosocial treatments (e.g., 2–10% with Assertive Community Treatment; Lehman and Steinwachs 1998). Success rate and discovery of innovative drugs has been disappointing; consequently, R&D by large pharmaceutical companies has been reduced sharply. There are also lingering questions about whether all patients require antipsychotic medication (e.g., Calton et al. 2008; Lehtinen et al. 2000), and about individual differences in the need for these drugs for long-term illness management and promotion of recovery (Fenton and McGlashan 1987; Harrow and Jobe 2007). Therefore, the focus of this group will be to explore answers to the following questions:

  • Should we treat the illness or treat symptoms and disabilities?
  • How can we promote greater investment in treatment development and optimizing service delivery?
  • Personalized treatment for people with schizophrenia: How do we get there?
  • Is more neuroscience the only answer? Are other bases of new interventions needed (e.g., a greater understanding of phenomenology; newer models of normal and abnormal belief formation and modification, etc.)?
  • How can the drug development process be restructured to increase successful treatment?
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References

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