Altering the course of schizophrenia: progress and perspectives

• Published in: Nature reviews. Drug discovery Vol. 15; no. 7; pp. 485 - 515
• Main Authors: Millan, Mark J., Andrieux, Annie, Bartzokis, George, Cadenhead, Kristin, Dazzan, Paola, Fusar-Poli, Paolo, Gallinat, Jürgen, Giedd, Jay, Grayson, Dennis R., Heinrichs, Markus, Kahn, René, Krebs, Marie-Odile, Leboyer, Marion, Lewis, David, Marin, Oscar, Marin, Philippe, Meyer-Lindenberg, Andreas, McGorry, Patrick, McGuire, Philip, Owen, Michael J., Patterson, Paul, Sawa, Akira, Spedding, Michael, Uhlhaas, Peter, Vaccarino, Flora, Wahlestedt, Claes, Weinberger, Daniel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2016; Nature Publishing Group
• Subjects: 631/154/109; 631/378/1689; 692/308/153; 692/699/476; Antipsychotic Agents - therapeutic use; Biomedicine; Biotechnology; Cancer Research; Care and treatment; Development and progression; Humans; Life Sciences; Medicinal Chemistry; Medicine, Preventive; Methods; Molecular Medicine; Pharmacology/Toxicology; Preventive health services; review-article; Schizophrenia; Schizophrenia - diagnosis; Schizophrenia - drug therapy
• ISSN: 1474-1776; 1474-1784; 1474-1784
• DOI: 10.1038/nrd.2016.28

Key Points Schizophrenia is a debilitating and chronic disorder that is accompanied by psychosis and a broad spectrum of behavioural, cognitive and social deficits. It usually strikes in young adulthood. Currently, treatment is exclusively symptomatic, and medication has no direct, lasting influence on causal pathophysiology. Improved knowledge of the developmental anomalies provoked by genetic, epigenetic and environmental triggers of schizophrenia has fostered interest in potential 'disease-modifying' strategies for either slowing its progression or preventing its appearance in vulnerable young adults. Although awaiting further confirmation, clinical studies of pharmacotherapeutic and psychosocial and/or cognitive-behavioural interventions in young, high-risk individuals seeking help have collectively yielded evidence for a reduction in the transition to psychosis. Nonetheless, only a third or so of clinically high-risk individuals convert, so it is important to improve the prediction of transition at the level of individuals by the use of biomarkers. Multi-modal approaches combining, for example, circulating biomarkers, sensory/cognitive deficits and brain imaging hold particular promise. Although animal models for schizophrenia have limitations, diverse pharmacological treatments applied during adolescence preclude the appearance of a schizophrenia-like phenotype in adult rodents. Studies exploiting these in vivo models, as well as novel cellular paradigms such as human induced pluripotent stem cells, are refining our understanding of the cellular substrates leading to schizophrenia, and hence unveiling potentially novel targets for medication. In conclusion, though much work still remains to be undertaken, recent progress is raising the hope that it may eventually be possible to interrupt the course of schizophrenia, as well as other disorders characterized by psychosis. Of particular interest would be hybrid strategies that both relieve distress in young, at-risk individuals and reduce their conversion. Advances in the understanding of the genetic and environmental causes of schizophrenia, and their relationship to aberrant patterns of neurodevelopment, have led to growing interest in the possibility that 'disease-modifying' strategies could alter the course to — and of — this debilitating disorder, rather than just alleviating its symptoms. This article provides a broad-based consideration of the challenges and opportunities inherent in such efforts. Despite a lack of recent progress in the treatment of schizophrenia, our understanding of its genetic and environmental causes has considerably improved, and their relationship to aberrant patterns of neurodevelopment has become clearer. This raises the possibility that 'disease-modifying' strategies could alter the course to — and of — this debilitating disorder, rather than simply alleviating symptoms. A promising window for course-altering intervention is around the time of the first episode of psychosis, especially in young people at risk of transition to schizophrenia. Indeed, studies performed in both individuals at risk of developing schizophrenia and rodent models for schizophrenia suggest that pre-diagnostic pharmacotherapy and psychosocial or cognitive-behavioural interventions can delay or moderate the emergence of psychosis. Of particular interest are 'hybrid' strategies that both relieve presenting symptoms and reduce the risk of transition to schizophrenia or another psychiatric disorder. This Review aims to provide a broad-based consideration of the challenges and opportunities inherent in efforts to alter the course of schizophrenia.