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Reconceptualizing Schizophrenia
Schizophrenia Research 127 (2011) 1–2
Contents lists available at ScienceDirect
Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Guest Editorial
Reconceptualizing Schizophrenia Over the past five decades, antipsychotic medications have proven to be a mixed blessing: while clinicians have been able to treat aspects of psychosis giving patients with schizophrenia partial relief, researchers have tended to focus more on the mechanisms of the medications rather than defining the biology of the disorder. As a result, in 2011, we still lack a basic understanding of the pathophysiology of schizophrenia. In their paper in this issue, Dr. Keshavan and his colleagues present a comprehensive summary and integration of the many conceptualizations of schizophrenia and an analysis of the roadblocks that have impeded the development of a unitary model of the disorder. This contribution is an excellent capstone to their series of “Just the Facts” articles (Keshavan et al., 2008; Tandon et al., 2008a,b, 2009, 2010). In the current article, the authors propose ten steps to move the field toward a reconceptualization of schizophrenia that may help us progress past the hurdles presented by the disease's multidimensional heterogeneity and elusive neuropathology. The time is indeed ripe to examine our conceptualization of schizophrenia in order to capitalize on new discoveries in genomics, neuroscience and intervention. Many of the proposed steps are consistent with the National Institute of Mental Health (NIMH) vision for the future of schizophrenia research (Insel, 2010). Dr. Keshavan and his co-authors raise the issue of heterogeneity and encourage researchers to take on this issue directly rather than rely on it as an explanation for inconsistent findings. The challenges of heterogeneity, not only in schizophrenia but within and across diagnostic categories, are part of the motivation behind the NIMH's Research Domain Criteria (RDoC) initiative (http://www.nimh.nih.gov/research-funding/rdoc. shtml). The intent of the RDoC is to accelerate the pace of new discoveries by fostering research that translates findings from basic science into new treatments addressing fundamental mechanisms and cutting across current diagnostic categories. RDoC will create a framework for integrating genomics, neuroscience, and behavioral science, without regard to current diagnostic categories. Many of the steps proposed by Dr. Keshavan and his colleagues can be taken using the RDoC framework. As they note, the delineation of the relationships between abnormal gamma synchrony, inefficient task-related prefrontal activation and working memory impairment – an interdisciplinary endeavor that is grounded in neural circuitry and agnostic with regards to diagnostic classification – is an excellent example of an innovative, RDoC-based approach. The reconceptualization of schizophrenia and adoption of the RDoC approach promise to help investigators make progress in four areas that are of high priority for NIMH, specifically: identification of biomarkers, development of novel therapies, early detection and intervention, and recovery-focused approaches. A major impediment to progress in understanding and treating schizophrenia is the lack of biomarkers of the illness and its variants. Genetic, physiological, cognitive or anatomical biomarkers of schizo0920-9964/$ – see front matter. Published by Elsevier B.V. doi:10.1016/j.schres.2011.01.027
phrenia could help speed the development of new interventions by allowing subtyping of patients for the purpose of predicting treatment responsiveness, identifying affected individuals in the prodrome, and serving as treatment targets or surrogate endpoints for the purpose of expediting proof of concept studies (Breier, 2005). The search for biomarkers has proven challenging as many promising candidates have been shown to be unreliable, non-specific to schizophrenia, or insensitive to intervention. The RDoC approach will help to advance the search for biomarkers by reframing the way that we think about disorders: as dimensional entities linked to neural circuits rather than categorical classifications linked to clinical phenomena. We face an urgent need for novel therapies, especially those that target cognitive impairment. The generally disappointing results of pharmacological interventions for cognitive impairment reinforce the importance of pursuing new avenues using agents that promote neuroprotection and neuroplasticity (Goff et al., in press). Nonpharmacological remediation programs show promise for alleviating cognitive impairment (Wykes and Huddy, 2009) but a great deal of work remains to be done in order to determine the “active ingredients” among the myriad interventions, maximize the longterm benefits for patients' day-to-day functioning, and examine the impact of targeted remediation programs, especially those that target early perception with the goal of normalizing “downstream” cognitive processes. There is also promise in approaches that combine psychosocial and/or pharmacological interventions, for example, use of psychosocial interventions to improve medication adherence or pharmacological enhancements to cognitive remediation programs. Our best hope for changing the trajectory of illness progression and minimizing damage to patients' social, educational, and vocational functioning is early detection and intervention. Identifying and engaging patients early in the course of illness are major challenges and there are many unanswered questions about the feasibility and long-term effects of early intervention. The Recovery After an Initial Schizophrenia Episode (RAISE) research project (http://www.nimh.nih.gov/health/ topics/schizophrenia/raise/index.shtml) is an exemplary effort to address these important issues with an eye toward large scale dissemination and we look forward to seeing how the lessons learned from this work and other similar projects will inform progress toward the development and implementation of effective early intervention. Dr. Keshavan and colleagues paint an ambitious and aspirational picture of personalized diagnosis and treatment that is consistent with the growing emphasis on recovery-based approaches to the treatment of mental disorders. This recovery model emphasizes a personalized, holistic, patient-directed approach to treatment and rehabilitation (Frese et al., 2009). Efforts are underway to concretize the meaning of recovery in psychiatric illness (Harvey and Bellack, 2009) and to develop methods to measure various aspects of recovery (Mausbach et al., 2009), and future research will reveal whether
2
Guest Editorial
interventions that incorporate recovery-based principles confer increased and novel benefits for patients, their families and care providers. While this approach has gained in popularity in recent years, it would be unfair to assume that our understanding matches our aspirations. We know only a small fraction of what we need to know to ensure recovery for most people with schizophrenia. The same might be said for many other serious medical illnesses, but for schizophrenia, where we lack biomarkers or treatments for the core mechanism of disease, a focus on recovery should not discourage a search for transformative diagnostics and therapeutics. To invoke the elephant metaphor referenced by Dr. Keshavan and colleagues, we agree that there are likely various species of this creature to be defined but, like most natural phenomena, it is ultimately knowable through the use of innovative and disruptive science.
Mausbach, B.T., Moore, R., Bowie, C., Cardenas, V., Patterson, T.L., 2009. A review of instruments for measuring functional recovery in those diagnosed with psychosis. Schizophr. Bull. 35, 307–318. Tandon, R., Keshavan, M.S., Nasrallah, H.A., 2008a. Schizophrenia, “Just the facts”: what we know in 2008. Part 2. Epidemiology and etiology. Schizophr. Res. 102, 1–18. Tandon, R., Keshavan, M.S., Nasrallah, H.A., 2008b. Schizophrenia, “Just the facts”: what we know in 2008: Part 1. Overview. Schizophr. Res. 100, 4–19. Tandon, R., Nasrallah, H.A., Keshavan, M.S., 2009. Schizophrenia, “Just the facts” 4: clinical features and conceptualization. Schizophr. Res. 110, 1–23. Tandon, R., Nasrallah, H.A., Keshavan, M.S., 2010. Schizophrenia, “Just the facts” 5: treatment and prevention, past, present, and future. Schizophr. Res. 122, 1–23. Wykes, T., Huddy, V., 2009. Cognitive remediation for schizophrenia: it is even more complicated. Curr. Opin. Psychiatry 22, 161–167.
Sarah E. Morris Division of Adult Translational Research and Treatment Development, NIMH, United States
References Breier, A., 2005. Developing drugs for cognitive impairment in schizophrenia. Schizophr. Bull. 31, 816–822. Frese, F.J., Knight, E.L., Saks, E., 2009. Recovery from schizophrenia: with views of psychiatrists, psychologists, and others diagnosed with this disorder. Schizophr. Bull. 35, 370–380. Goff, D.C., Hill, M., Barch, D., in press. The treatment of cognitive impairment in schizophrenia. Pharmacol. Biochem. Behav. Harvey, P.D., Bellack, A.S., 2009. Toward a terminology for functional recovery in schizophrenia: is functional remission a viable concept? Schizophr. Bull. 35, 300–306. Insel, T.R., 2010. Rethinking schizophrenia. Nature 468, 187–193. Keshavan, M.S., Tandon, R., Boutros, N.N., Nasrallah, H.A., 2008. Schizophrenia, “Just the facts”: what we know in 2008: Part 3. Neurobiology. Schizophr. Res. 106, 89–107.
Thomas R. Insel National Institute of Mental Health, United States Corresponding author. Tel.: +1 301 443 3673. E-mail address: [email protected]. 29 January 2011
Contents lists available at ScienceDirect
Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Guest Editorial
Reconceptualizing Schizophrenia Over the past five decades, antipsychotic medications have proven to be a mixed blessing: while clinicians have been able to treat aspects of psychosis giving patients with schizophrenia partial relief, researchers have tended to focus more on the mechanisms of the medications rather than defining the biology of the disorder. As a result, in 2011, we still lack a basic understanding of the pathophysiology of schizophrenia. In their paper in this issue, Dr. Keshavan and his colleagues present a comprehensive summary and integration of the many conceptualizations of schizophrenia and an analysis of the roadblocks that have impeded the development of a unitary model of the disorder. This contribution is an excellent capstone to their series of “Just the Facts” articles (Keshavan et al., 2008; Tandon et al., 2008a,b, 2009, 2010). In the current article, the authors propose ten steps to move the field toward a reconceptualization of schizophrenia that may help us progress past the hurdles presented by the disease's multidimensional heterogeneity and elusive neuropathology. The time is indeed ripe to examine our conceptualization of schizophrenia in order to capitalize on new discoveries in genomics, neuroscience and intervention. Many of the proposed steps are consistent with the National Institute of Mental Health (NIMH) vision for the future of schizophrenia research (Insel, 2010). Dr. Keshavan and his co-authors raise the issue of heterogeneity and encourage researchers to take on this issue directly rather than rely on it as an explanation for inconsistent findings. The challenges of heterogeneity, not only in schizophrenia but within and across diagnostic categories, are part of the motivation behind the NIMH's Research Domain Criteria (RDoC) initiative (http://www.nimh.nih.gov/research-funding/rdoc. shtml). The intent of the RDoC is to accelerate the pace of new discoveries by fostering research that translates findings from basic science into new treatments addressing fundamental mechanisms and cutting across current diagnostic categories. RDoC will create a framework for integrating genomics, neuroscience, and behavioral science, without regard to current diagnostic categories. Many of the steps proposed by Dr. Keshavan and his colleagues can be taken using the RDoC framework. As they note, the delineation of the relationships between abnormal gamma synchrony, inefficient task-related prefrontal activation and working memory impairment – an interdisciplinary endeavor that is grounded in neural circuitry and agnostic with regards to diagnostic classification – is an excellent example of an innovative, RDoC-based approach. The reconceptualization of schizophrenia and adoption of the RDoC approach promise to help investigators make progress in four areas that are of high priority for NIMH, specifically: identification of biomarkers, development of novel therapies, early detection and intervention, and recovery-focused approaches. A major impediment to progress in understanding and treating schizophrenia is the lack of biomarkers of the illness and its variants. Genetic, physiological, cognitive or anatomical biomarkers of schizo0920-9964/$ – see front matter. Published by Elsevier B.V. doi:10.1016/j.schres.2011.01.027
phrenia could help speed the development of new interventions by allowing subtyping of patients for the purpose of predicting treatment responsiveness, identifying affected individuals in the prodrome, and serving as treatment targets or surrogate endpoints for the purpose of expediting proof of concept studies (Breier, 2005). The search for biomarkers has proven challenging as many promising candidates have been shown to be unreliable, non-specific to schizophrenia, or insensitive to intervention. The RDoC approach will help to advance the search for biomarkers by reframing the way that we think about disorders: as dimensional entities linked to neural circuits rather than categorical classifications linked to clinical phenomena. We face an urgent need for novel therapies, especially those that target cognitive impairment. The generally disappointing results of pharmacological interventions for cognitive impairment reinforce the importance of pursuing new avenues using agents that promote neuroprotection and neuroplasticity (Goff et al., in press). Nonpharmacological remediation programs show promise for alleviating cognitive impairment (Wykes and Huddy, 2009) but a great deal of work remains to be done in order to determine the “active ingredients” among the myriad interventions, maximize the longterm benefits for patients' day-to-day functioning, and examine the impact of targeted remediation programs, especially those that target early perception with the goal of normalizing “downstream” cognitive processes. There is also promise in approaches that combine psychosocial and/or pharmacological interventions, for example, use of psychosocial interventions to improve medication adherence or pharmacological enhancements to cognitive remediation programs. Our best hope for changing the trajectory of illness progression and minimizing damage to patients' social, educational, and vocational functioning is early detection and intervention. Identifying and engaging patients early in the course of illness are major challenges and there are many unanswered questions about the feasibility and long-term effects of early intervention. The Recovery After an Initial Schizophrenia Episode (RAISE) research project (http://www.nimh.nih.gov/health/ topics/schizophrenia/raise/index.shtml) is an exemplary effort to address these important issues with an eye toward large scale dissemination and we look forward to seeing how the lessons learned from this work and other similar projects will inform progress toward the development and implementation of effective early intervention. Dr. Keshavan and colleagues paint an ambitious and aspirational picture of personalized diagnosis and treatment that is consistent with the growing emphasis on recovery-based approaches to the treatment of mental disorders. This recovery model emphasizes a personalized, holistic, patient-directed approach to treatment and rehabilitation (Frese et al., 2009). Efforts are underway to concretize the meaning of recovery in psychiatric illness (Harvey and Bellack, 2009) and to develop methods to measure various aspects of recovery (Mausbach et al., 2009), and future research will reveal whether
2
Guest Editorial
interventions that incorporate recovery-based principles confer increased and novel benefits for patients, their families and care providers. While this approach has gained in popularity in recent years, it would be unfair to assume that our understanding matches our aspirations. We know only a small fraction of what we need to know to ensure recovery for most people with schizophrenia. The same might be said for many other serious medical illnesses, but for schizophrenia, where we lack biomarkers or treatments for the core mechanism of disease, a focus on recovery should not discourage a search for transformative diagnostics and therapeutics. To invoke the elephant metaphor referenced by Dr. Keshavan and colleagues, we agree that there are likely various species of this creature to be defined but, like most natural phenomena, it is ultimately knowable through the use of innovative and disruptive science.
Mausbach, B.T., Moore, R., Bowie, C., Cardenas, V., Patterson, T.L., 2009. A review of instruments for measuring functional recovery in those diagnosed with psychosis. Schizophr. Bull. 35, 307–318. Tandon, R., Keshavan, M.S., Nasrallah, H.A., 2008a. Schizophrenia, “Just the facts”: what we know in 2008. Part 2. Epidemiology and etiology. Schizophr. Res. 102, 1–18. Tandon, R., Keshavan, M.S., Nasrallah, H.A., 2008b. Schizophrenia, “Just the facts”: what we know in 2008: Part 1. Overview. Schizophr. Res. 100, 4–19. Tandon, R., Nasrallah, H.A., Keshavan, M.S., 2009. Schizophrenia, “Just the facts” 4: clinical features and conceptualization. Schizophr. Res. 110, 1–23. Tandon, R., Nasrallah, H.A., Keshavan, M.S., 2010. Schizophrenia, “Just the facts” 5: treatment and prevention, past, present, and future. Schizophr. Res. 122, 1–23. Wykes, T., Huddy, V., 2009. Cognitive remediation for schizophrenia: it is even more complicated. Curr. Opin. Psychiatry 22, 161–167.
Sarah E. Morris Division of Adult Translational Research and Treatment Development, NIMH, United States
References Breier, A., 2005. Developing drugs for cognitive impairment in schizophrenia. Schizophr. Bull. 31, 816–822. Frese, F.J., Knight, E.L., Saks, E., 2009. Recovery from schizophrenia: with views of psychiatrists, psychologists, and others diagnosed with this disorder. Schizophr. Bull. 35, 370–380. Goff, D.C., Hill, M., Barch, D., in press. The treatment of cognitive impairment in schizophrenia. Pharmacol. Biochem. Behav. Harvey, P.D., Bellack, A.S., 2009. Toward a terminology for functional recovery in schizophrenia: is functional remission a viable concept? Schizophr. Bull. 35, 300–306. Insel, T.R., 2010. Rethinking schizophrenia. Nature 468, 187–193. Keshavan, M.S., Tandon, R., Boutros, N.N., Nasrallah, H.A., 2008. Schizophrenia, “Just the facts”: what we know in 2008: Part 3. Neurobiology. Schizophr. Res. 106, 89–107.
Thomas R. Insel National Institute of Mental Health, United States Corresponding author. Tel.: +1 301 443 3673. E-mail address: [email protected]. 29 January 2011