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, dep