We use research technologies to understand what happens when a brain becomes psychotic, and, with that knowledge, to improve the treatment and prevention of psychosis. Current work has focused on several brain imaging technologies, but this will likely expand to include measures of cortical thickness and brain white matter. As we are interested in the role of stress and the development of psychosis, our investigations will also include the brain stress-regulation system (cortisol and the hypothalamic-pituitary-axis), as well as general markers of inflammation that have been associated with psychosis. Lastly, rapidly expanding knowledge from genetic and genomic studies has implicated many possible pathways to psychosis, which can identify risk factors and mechanisms of the illness. In future collaborations, we anticipate bringing these genetic studies into our research effort to inform our research into mechanisms and, most importantly, the development of treatment predictors and new therapies. PREP is firmly committed to advancing our knowledge in a way that will make a difference to prevent the suffering – and even the occurrence – of serious mental disorders like schizophrenia.
Participation in the Early Detection, Intervention and Prevention of Psychosis Program
In 2007, the Robert Wood Johnson Foundation funded the Early Detection, Intervention and Prevention of Psychosis Program (EDIPPP) - an ambitious national study to test the hypothesis that early intervention in the psychosis risk state could improve outcomes and reduce conversions to full-blown psychosis. Partnering with our local community mental health board, the Washtenaw Community Health Organization (WCHO), we were selected as one of the 6 sites. Known locally as ‘Michigan Prevents Prodromal Progression,’ or ‘M3P,’ the program recruited 55 young people. Just recently published results (McFarlane et al, 2014) show that the intervention worked, adding to a growing international literature showing risk reductions of 46-66% in 11 randomized clinical trials of individuals with APS. Enrollment in EDIPPP/M3P ended in 2010, but the project established our center within a network of other early intervention programs (Maine Medical Center, University of California, Davis, Mid-Valley Behavioral Care Network in Salem, Oregon, Zucker Hillside Hospital, and University of New Mexico), and provided the impetus for the development of PREP.
Current / Developing Studies
Brain imaging in APS and early psychosis
In July of last year, the National Institute of Mental Health awarded us a $428,000 grant to conduct brain imaging studies of persons with early psychosis and APS. Funding was possible for this study because of the basic infrastructure support available to us, and the 2-year grant has allowed us to enhance our operations in the service of PREP goals. The brain imaging study is using magnetic resonance spectroscopy (MRS) and functional magnetic resonance imaging (fMRI) to study disordered brain chemistry (GABAergic systems) and function, building upon our previous scientific work. We have focused on the critical role of emotion and distress in psychosis, functions very relevant for social functioning and overall outcome.
Understanding the brain systems that underlie psychosis is key to designing better interventions, both pharmacologic and psycho-social (such as CBT).
CBT Treatment for APS and early psychosis – Mechanisms of action
Extending our clinical work with CBT, we are designing innovative implementations with an eye to improving CBT. We have completed work on a CBT manual, and are in the process of setting up initial trials with this manual. We will be conducting work to examine mechanisms of CBT, using fMRI brain scans and electrophysiology. An improved understanding of how CBT changes the brain can help improve CBT itself. For example, cognitive training paradigms may be used to enhance the effect of CBT, and fMRI studies may be used to determine how to design those enhancement strategies. We are also developing a paradigm to use exercise to enhance the effect of CBT. Making CBT more effective means that we will have more therapeutic tools that can stop the progression of psychosis.
First Episode Treatment Network
A critical part of any research activity is gaining the power of numbers by collaborating within research networks. We are in discussions to join a first episode treatment network coordinated by Dr. John Kane of Zucker Hillside Hospital in New York. This network will provide access to innovative new pharmacotherapies for qualifying patients.
Brain imaging studies of augmentation agents
We have initiated work to study specific neurotransmitter systems implicated in schizophrenia, such as GABA, the major inhibitory neurotransmitter in the brain. In clinical practice, this neurotransmitter is affected by several classes of drugs, including benzodiazepines (lorazepam, clonazepam, diazepam). Benzodiazepines have been effectively used as augmentation agents with antipsychotics, although side effects (sedation, memory loss) and abuse potential limit their use. A better drug to target GABA is needed, and one of the steps to developing such an agent is understanding how existing drugs affect GABA systems. We are now planning treatment studies to track down the mechanisms of the beneficial effects of GABAergic drugs (and others). This improved understanding of drug mechanisms should lead to the design of better drugs, with stronger therapeutic effects and fewer side effects.
Brain mapping social function with fMRI and ERP
One of the notable functions disrupted by psychosis is the ability to socialize and effectively maintain interpersonal relationships. Known broadly as social cognition, this important domain consists of many specific components, such as perceiving eye gaze. We have shown how gaze perception is disrupted in psychosis, and planned work will use fMRI to extend studies we have begun with event-related potentials (ERP). Identifying the disrupted components of social cognition will allow the design of behavioral and pharmacologic interventions that can target this part of psychosis. To date, there are no known treatments that specifically improve social cognition in psychosis, so identifying the disrupted components of social cognition will allow the design of behavioral and pharmacologic interventions that can target this part of psychosis.
Metabolism, cardiovascular health, and antipsychotic treatment
One of the unfortunate side effects of antipsychotics is a higher risk of metabolic syndrome (‘pre-diabetes’) and diabetes. The relationship between metabolism, antipsychotic treatment, and psychosis also reveals important clues about psychosis itself, such as links between inflammation and cardiovascular health. In collaboration with Dr. Vicki Ellingrod in the School of Pharmacy, we are carrying out a study of metabolic factors that influence cardiovascular health, exploring the potential beneficial role of folic acid supplementation for individuals on antipsychotic therapy. This current work focuses on individuals with long-standing schizophrenia, but future work will also focus on some of the genetic risk factors and possible preventive strategies for individuals with early psychosis who require antipsychotic therapy.
Recent Scientific Presentations and Publications
Niendam TA, Ragland JD, Floyd E, Auther A, Cornblatt B, Adelsheim S, Calkins R, Melton R, Sale T, Spring-Nichols E, Taylor SF, Cook W, McFarlane WR, Carter CS: Multi-site investigation of impaired prefrontal functioning as a potential marker of long-term outcome in psychosis risk state, Presentation at the Society of Biological Psychiatry Annual Meeting, San Francisco, CA, May 2013
Demeter E, Guthrie SK, Taylor SF, Sarter M, Lustig C: Increased distractor vulnerability but preserved vigilance in patients with schizophrenia: Evidence from a translational sustained attention task, Schizophrenia Research, 144:136-41, 2013
Taylor SF, Demeter E, Phan KL, Tso IF, Welsh RC: Abnormal GABAergic function and negative affect in schizophrenia, Neuropsychopharmacology, 39(4):1000-1008, 2014.
Tso IF, Carp J, Taylor SF, Deldin PJ: The Role of Visual Integration in Gaze Perception and Emotional Intelligence in Schizophrenia, Schizophrenia Bulletin, 40(3):617-625, 2014.
Tso IF, Fang Y, Phan KL, Welsh RC, Taylor SF: Abnormal GABAergic function and face processing in schizophrenia. Presentation at the Society of Biological Psychiatry Annual Meeting, New York, NY, May 2014.
McFarlane WR, Levin B, Travis L, Lucas FL, Lynch S, Verdi M, Williams D, Adelsheim S, Calkins R, Carter CS, Cornblatt B, Taylor SF, Author AM, McFarland B, Melton R, Migliorati M, Niendam T, Ragland JD, Sale T, Salvador M, Spring L: Clinical and functional outcomes after 2 years in the national Early Detection and Intervention for the Prevention of Psychosis effectiveness trial, Schizophrenia Bulletin, in press.
Tso IF, Grove TB, Taylor SF: Differential hedonic experience in schizophrenia and bipolar disorder. Psychiatry Research, in press.
Tso IF, Taylor SF, Grove TB, Niendam T, Adelsheim S, Auther A, Cornblatt B, Carter CS, Calkins R, Ragland D, Sale T, McFarlane WR: Factor Analysis of the Scale of Prodromal Symptoms: Data from the Early Detection and Intervention for the Prevention of Psychosis Program (EDIPPP), Early Intervention in Psychiatry, submitted.
Tso IF, Calwas AM, Chun J, Mueller SA, Taylor SF, Deldin PJ: Altered attentional and perceptual processes as indexed by N170 during gaze perception in schizophrenia: Relationship with perceived threat and paranoid delusions. Journal of Abnormal Psychology, under revision.