What Is Necessary to Enhance Development and Utilization of Treatment?

This chapter is framed by four perspectives. The fi rst views schizophrenia as a heterogeneous disorder that may present itself very differently across individuals. Heterogeneity has important implications for treatment approaches: for treatments to be optimally effective, they need to be tailored to the individual. The second perspective integrates what are often considered separate and divergent approaches to treatment in schizophrenia, bringing together, in both complementary and synergistic combination, the biological and the psychosocial. Within this perspective, clinical treatment models capable of being personalized to heterogeneous, individual profi les are proposed. The third perspective is a practical one that examines how the two extreme ends of the treatment continuum, treatment development and service delivery, can be optimized to ensure enhanced outcomes for people with schizophrenia. Finally, treatment is viewed from the perspective of the whole person. This not only has implications for mental and physical well-being and quality of life in people with schizophrenia, but also takes into consideration the social context in which these individuals are placed. Overall, the approach offered, with its integration across multiple domains, emphasizes the potential for improved recovery rates and hope for prevention and cure in this devastating disorder. Schizophrenia: Cure and Recovery A Cure for Schizophrenia This is a very exciting time for schizophrenia research. The journal Nature has declared the decade beginning in 2010 to be the “decade for psychiatric From “Schizophrenia: Evolution and Synthesis,” S. M. Silverstein, B. Moghaddam, and T. Wykes, eds. 2013. Strüngmann Forum Reports, vol. 13, J. Lupp, series ed. Cambridge, MA: MIT Press. 978-0-262-01962-0. 274 V. A. Morgan et al. disorders” in the hope that the neuroscience tools and paradigms developed in the “decade of the brain” can now be applied to identify new and better treatments for mental illness. Nowhere is this more urgent than for schizophrenia. The number of mechanistically novel pharmacological treatments for schizophrenia has been disappointingly low. Government-sponsored large-scale naturalistic trials have suggested that there is little difference in effi cacy between newer antipsychotic agents compared to older drugs. Most patients with schizophrenia still do not marry, have a severely compromised educational and job trajectory, and die on average 15 years earlier than the general population. The illness defi nition is currently based on a combination of psychopathological features observed by patients and their caregivers as well as duration criteria. To be useful for treatment, our understanding of the individual processes lumped together under the label “schizophrenia” will have to be refi ned for individualization to be possible. The most useful entry points into this process are the clear biological risk factors for the illness: genetic and environmental factors. The pursuit of risk mechanisms is therefore a major strategy to individualize treatment and to fi nd new treatments (Meyer-Lindenberg 2010a) because truly novel targets for molecular therapies can only emerge from the detailed understanding of the molecular mechanisms of the illness; genes with their products, if they have been found through hypothesis-free searches, are pointers to such novel mechanisms. Ever better designed, better characterized, and larger multinational studies are necessary and are being pursued to identify new genetic and environmental risk factors. Longitudinal studies which focus on the period around adolescence are underway in several countries and are expected to give us a better understanding of the way these risk factors interact with brain development. Another potentially paradigm-changing advance is that, through techniques such as induced pluripotent stem cells, we are now able to generate neurons from a person with a known disease history and genetic makeup and study the metabolism and activity in these cells across their development, giving us access to the “target tissue” of psychiatry in a way that seemed impossible even a few years ago (Brennand et al. 2011). The pursuit of these new targets necessitates, in principle, the use of the entire armamentarium of modern neuroscience. For the fi rst time in history, psychiatrists truly need and can use techniques from whole brain genome sequencing and epigenetics to expression mapping, proteomics, and lipidomics to pursue their goals. One critical and specifi c task for psychiatric neuroscience is to integrate this information with an understanding on the neural systems level (e.g., in the technique of “ imaging genetics”) so as to bridge the gap between cellular–molecular mechanisms and disturbed behavior. An understanding of the mechanisms underlying schizophrenia is also critical for the generation of better animal models for use in the identifi cation of new drug molecular candidates. Schizophrenia affects human-specifi c faculties From “Schizophrenia: Evolution and Synthesis,” S. M. Silverstein, B. Moghaddam, and T. Wykes, eds. 2013. Strüngmann Forum Reports, vol. 13, J. Lupp, series ed. Cambridge, MA: MIT Press. 978-0-262-01962-0. Enhancing Development and Utilization of Treatment 275 such as language and higher cognition. Clearly, these features cannot be modeled in animals. Animal models currently used for schizophrenia have been directly derived from the profi le of the currently used antipsychotic agents that are related to dopaminergic blockade. There is little evidence that these behavioral features are a good model for schizophrenia. A better understanding of mechanisms could be decisive in designing a new generation of animal models that are more predictive for effi cacy through delineating neural systems that are implicated in schizophrenia. Sometimes, however, “the best experimental animal is the human.” This is especially true in psychiatric drug development, where the success rate in predicting which new medications are effective is disappointing. A new generation of applying systems-level neuroscience in early drug trials in humans will constitute a revival and focusing of experimental medicine in psychiatry. This concept, which has been extraordinarily fruitful in bringing about advances in oncology and hematology, is ripe for application for schizophrenia. It is entirely possible that, in the end, “the answer” about schizophrenia is suffi ciently complex as to require the study of the multiple risk pathways that combine in a given person to push him or her over the threshold to develop the illness. For schizophrenia research, computational approaches and especially computational neuroscience will be tremendously important to be able to quantify the effects that perturbations on genetic and environmental levels have on systems-level function. A comprehensive characterization of the neural risk architecture of schizophrenia through these various approaches, and their integration, provides a crucial translational research strategy for advancing new treatments for the illness. Recovery in Schizophrenia Over the past twenty years, the recovery movement has evolved to become a driving force in changing how major mental illnesses, including schizophrenia, are understood and treated (Silverstein and Bellack 2008). “Consumers” of mental health services (also called “service users”) have protested against the pessimistic messages they have been given about the long-term outcome of serious mental illness, pointing to longitudinal research that shows symptom remission and functional improvement in signifi cant proportions of people with schizophrenia (Davidson et al. 2005; Deegan 1991). Consumers have also argued for the reduction of coercive interventions and a change from hierarchical decision making to more collaborative approaches that respect their individual preferences and their need to determine their own treatment priorities (Chamberlin 1997b; McLean 1995). Perhaps the most signifi cant impact of this movement has been its challenge of traditional medical perspectives on recovery from mental illness that have emphasized remission of symptoms and associated impairments, in favor of more nuanced and personally meaningful defi nitions. For example, remission from schizophrenia has been defi ned in the From “Schizophrenia: Evolution and Synthesis,” S. M. Silverstein, B. Moghaddam, and T. Wykes, eds. 2013. Strüngmann Forum Reports, vol. 13, J. Lupp, series ed. Cambridge, MA: MIT Press. 978-0-262-01962-0. 276 V. A. Morgan et al. medical community in terms of meeting distinct thresholds of sustained improvement in symptomatic, cognitive, and functional domains of the disorder (Andreasen et al. 2005). Although there is less agreement about how recovery from schizophrenia should be defi ned, it has been broadly conceptualized as encompassing remission of symptoms and functional impairments, while also extending to improved quality of life (Leucht and Lasser 2006). New conceptualizations of recovery focus on personal growth, and establishing meaning and sense of purpose in life, despite having a mental illness (Anthony 1993). The desire for a more personally meaningful defi nition of recovery than symptom remission frequently evokes different areas of psychosocial functioning. For example, the President’s New Freedom Commission on Mental Health (2003:6) defi nes recovery as “...the process in which people are able to live, work, learn, and participate fully in their communities.” Thus, according to the recovery movement, improvements in psychosocial functioning are a greater treatment priority than symptom management or remission. Is Prevention Feasible? Prevention of illness is preferable to cure, but what is the disease target of the prevention? Is it psychosis generally or schizophrenia specifi cally? The two are not the same, and the focus of the intervention may differ, depending on the disease target. Most studies of risk intervention prior to illness onset focus on psychotic-like experiences. However, to date, there has been minimal success in identifying which young people will convert to psychosis within high-risk and prodromal samples (i.e., help-seeking groups whose at-risk status is determined in the clinic, generally on the basis of psychotic symptoms). Moreover, it remains unresolved whether these interventions prevent schizophrenia or ameliorate its course. Psychotic symptoms may be too far along the illness trajectory to be a viable target for the prevention of schizophrenia. It is likely that, by the time fi rst episode cases are manifest, a critical point for primary prevention has been missed. In this regard, several studies have demonstrated that psychosis is preceded by cognitive and social dysfunction by almost a decade, suggesting that prevention may need to start years earlier, targeting cognition and social function, rather than the more common target of psychotic-like experiences. This does not reject the at-risk state and prodrome as targets for secondary prevention, which we examine in some detail later. Defi ning Prevention We use the term primary prevention to refer to broad public health interventions that reduce incidence of illness or comparable problems in the general population, for example, nutritional programs, afterschool activity programs, From “Schizophrenia: Evolution and Synthesis,” S. M. Silverstein, B. Moghaddam, and T. Wykes, eds. 2013. Strüngmann Forum Reports, vol. 13, J. Lupp, series ed. Cambridge, MA: MIT Press. 978-0-262-01962-0. Enhancing Development and Utilization of Treatment 277 general health education. We use this to refer to interventions in the pre-prodromal period in schizophrenia. We use the term secondary prevention to refer to focused interventions that target subpopulations identifi ed as being at risk for developing illnesses or comparable problems, for the purpose of preventing the actual onset. We use this to refer to interventions in the at-risk or prodromal period in schizophrenia. We use the term tertiary prevention to refer to focused interventions that target subpopulations after the onset of illnesses or comparable problems, for the purpose of minimizing morbidity or chronicity. We use this to refer to interventions after illness onset in schizophrenia. A Target for Primary Prevention in Schizophrenia: Relative Decline in Cognition in Early Adolescence As described by Kahn (this volume), a decline in cognition relative to peers (developmental lag) in late childhood/ early adolescence may be the strongest indicator of early manifestations of the illness. We distinguish cognitive decline from enduring cognitive defi cit. While both forms of cognitive defi cit may increase the risk of schizophrenia, our focus here is on cognitive decline as it is likely to be more refl ective of eventual psychosis, and may be most amenable to primary prevention. We note also that cognitive decline is distinguished from normal variability in IQ that has been observed in adolescence (Ramsden et al. 2011). Our proposal, in its current state, is not a model of clinical intervention, but a research strategy with the potential to lead to primary prevention. The strategy involves identifying, on the basis of school grades or similar measures, children in late childhood/early adolescence living in the general community, who exhibit cognitive decline relative to their peers. These children would be the target of school-based interventions. It is important to note that schizophrenia would neither be a necessary nor sole endpoint in this proposed strategy, as the intervention is likely to have an impact on a range of disorders. By taking this approach, however, we may learn how to predict and prevent schizophrenia on the basis of relative cognitive decline. What Is This Thing Called Schizophrenia? The proposed strategy outlined above considers cognitive decline as a closed construct within an open construct. If a putative illness, in this case schizophrenia, is an open construct, its exact features and parameters are indistinct or unknown, and the distinction between primary, secondary, and tertiary prevention is unclear. For example, if cognitive decline is understood to be an early expression of schizophrenia, interventions directed at it are, by defi nition, after onset, thus constituting tertiary prevention aimed at arresting further cognitive decline and/or further progress of the illness. On the other hand, if cognitive From “Schizophrenia: Evolution and Synthesis,” S. M. Silverstein, B. Moghaddam, and T. Wykes, eds. 2013. Strüngmann Forum Reports, vol. 13, J. Lupp, series ed. Cambridge, MA: MIT Press. 978-0-262-01962-0. 278 V. A. Morgan et al. decline is understood to be a risk factor or part of the prodrome, intervention is understood to be primary or secondary prevention. However, these are semantic distinctions. The value of identifying and responding to cognitive decline has obvious importance, regardless of whether it is a risk factor, a prodrome, or an early expression of the actual illness. Specifi city to Schizophrenia It appears that cognitive dysfunction—at least prior to psychosis onset—distinguishes schizophrenia from bipolar disorder. A consistent pattern emerging from population-based studies worldwide is that low IQ constitutes a risk factor for schizophrenia, but not for bipolar disorder or depression (Reichenberg et al. 2002; Zammit et al. 2004; Sørensen et al. 2012). Moreover, one study found that children with excellent school performance had almost four times the risk of developing bipolar illness compared to children with average grades (MacCabe et al. 2010). A number of studies have reported a decline in cognitive function prior to the onset of schizophrenia (Fuller et al. 2002; Reichenberg et al. 2010). Whether a decline in cognitive function precedes the onset of bipolar disorder has not been addressed in population-based studies. However, a study of monozygotic and dizygotic twins discordant for bipolar disorder (Van Oel et al. 2002) found, in contrast to fi ndings from a similar study of discordant schizophrenia twins, that the twin who went on to develop bipolar disorder, compared to the unaffected co-twin, did not do worse at school and only showed a temporary decline in functioning, with no long-term underperformance (Vonk et al. 2012). Taken together, evidence strongly suggests that low IQ and cognitive underperformance during adolescence and at fi rst presentation of psychosis differentiates schizophrenia from bipolar disorder.