Neuroimaging Biomarkers for Early Drug Development in Schizophrenia

Abstract

Given the relative inability of currently available antipsychotic treatments to adequately provide sustained recovery and improve quality of life for patients with schizophrenia, new treatment strategies are urgently needed. One way to improve the therapeutic development process may be an increased use of biomarkers in early clinical trials. Reliable biomarkers that reflect aspects of disease pathophysiology can be used to determine if potential treatment strategies are engaging their desired biological targets. This review evaluates three potential neuroimaging biomarkers: hippocampal hyperactivity, gamma-band deficits and default network abnormalities. These deficits have been widely replicated in the illness, correlate with measures of positive symptoms, are consistent with models of disease pathology, and have shown initial promise as biomarkers of biological response in early studies of potential treatment strategies. Two key features of these deficits, and a guiding rational for the focus of this review, is that the deficits are not dependent upon patients' performance of specific cognitive tasks, and have analogues in animal models of schizophrenia, greatly increasing their appeal for use as biomarkers. Using neuroimaging biomarkers such as those proposed here to establish early in the therapeutic development process if treatment strategies are having their intended biological effect in humans may facilitate development of new treatments for schizophrenia.

Aligning physiology with psychology: Translational neuroscience in neuropsychiatric drug discovery

“…Neuroimaging has developed into an invaluable tool for drug discovery and development Fox et al, 2009;Hargreaves et al, 2010;McArthur, 2012;Tregellas, 2014;von Kienlin and Risterucci, 2010;Wan et al, 2010;Wong et al, 2008a).…”

Targeting Functional Biomarkers in Schizophrenia with Neuroimaging

“…For example, intrinsic hippocampal hyperactivity and default network hyperactivity are two promising, potential biomarkers for schizophrenia that have been identified in large part by fMRI [28]. The effectiveness of these biomarkers depends not only upon their ability to be associated with clinical outcomes, but also their ability to predict treatment response.…”

“…The effectiveness of these biomarkers depends not only upon their ability to be associated with clinical outcomes, but also their ability to predict treatment response. As reviewed by Tregellas [28], both hippocampal hyperactivity and dysfunction within large-scale networks have demonstrated promise in fulfilling these criteria. These results, however, are in need of validation by larger studies, particularly in determining how effects of both established and investigational therapies may target these biomarkers to produce treatment effects.…”

“…The hippocampus is one of the most well-studied areas of the brain, with a well-described anatomy and physiology. Hippocampal dysfunction and abnormal circuitry are commonly reported in schizophrenia [28,52–55]. Furthermore, the medial temporal lobe in general and the hippocampus in particular show the most prominent grey matter deficits in schizophrenia [56,57].…”

Effects of a ketogenic diet on auditory gating in DBA/2 mice: A proof-of-concept study

“…Neuroimaging studies in human patients frequently have observed increased activity in the hippocampus in patients with schizophrenia, relative to comparison subjects (reviewed by Heckers and Konradi (2014); Tamminga et al (2012); Tamminga et al (2010); Tregellas (2014)). The magnitude of this abnormality may predict positive (Ebmeier et al, 1993; Friston et al, 1992; Gur et al, 1995; Kawasaki et al, 1996; Liddle et al, 1992; Molina et al, 2005; Schobel et al, 2013; Schobel et al, 2009), negative (Schobel et al, 2009; Tregellas et al, 2014), and cognitive (Tregellas et al, 2014) symptoms.…”