Scott Woods - US grants

clinical anxiety; alpha antiadrenergic agent; yohimbine; hyperpnea; technetium; human subject; behavior test; single photon emission computed tomography;

This is one of four independent but identical applications for a multi- center treatment study of panic disorder (PD) comprising the first study designed to assess the relative efficacy of a pharmacologic treatment, a cognitive behavioral panic control treatment and their combination for patients with PD. The study is designed as a 12 week acute treatment trial, followed by 6 months of maintenance treatment and 6 months of follow-up. PD is a prevalent chronic and debilitating disorder. Although some studies are available documenting the efficacy of both pharmacological and behavioral treatments for patients with agoraphobia, behavioral treatments for agoraphobia are very different from the newly developed cognitive behavioral treatments for PD. Preliminary studies suggest that these treatments may be quite effective. Surprisingly, few studies exist evaluating pharmacological treatments for PD without agoraphobia. Yet, a variety of evidence suggests that drugs are effective for panic attacks. It is also possible that the combination of psychological and pharmacological treatment will provide the optimal approach for many patients or that relapse rates after treatment discontinuation will differ. Central to this proposal is the collaboration of four research sties (SUNY Albany, Cornell, Hillside/Columbia and Yale) representing both psychological and pharmacological orientations. The sites will enroll a total of 600 patients over 4 years. Patients will be randomly assigned to one of five treatment cells: imipramine (IMI) with medical management, pill placebo (PLA) with medical management, Panic Control Treatment (PCT) or a combination of PCT with either IMI or PLA. In addition to establishing relative efficacy, this design will allow us to establish guidelines for treatment of PD at sites wit somewhat different orientations, identify comparative mechanisms of action of psycho-and pharmacotherapy, and introduce innovative methods to integrate medication and psychosocial treatment modalities for PD patients. An additional goal will be to examine the implication of prior psychoactive substance abuse for treatment outcome as well as the utilization of substances as coping mechanisms for anxiety and panic.

The goal of this study is to evaluate the efficacy of the newly available benzodiazepine (BZ) antagonist flumazenil for rapidly detoxifying patients from BZ agonist drugs. Conventional BZ detoxification involves prescription of a long-acting BZ and gradual taper. This is problematic in outpatients being treated for substance abuse because patients often continue to supplement the prescribed benzodiazepines with illicit ones, and inpatient hospitalization is not always readily available. Flumazenil (previously known as Ro 15-1788) was recently released by the FDA in February 1992 (trade name "Mazicon") to reverse BZ overdose. The initial dose of flumazenil can induce a brief BZ withdrawal. Subsequent doses of flumazenil, however, have evoked a greatly attenuated withdrawal in studies using BZ dependent nonhuman primates, suggesting that BZ dependence and withdrawal liability had been reversed by the initial flumazenil dose. While this reversal of dependence is clearly potentially beneficial, the initial withdrawal precipitation carries some risk. Six of 446 patients receiving flumazenil in cases of suspected BZ overdose had seizures. Barbiturate pretreatment should counteract the reduction in chloride channel opening accompanying BZ receptor occupation by flumazenil in BZ dependent subjects and thus attenuate the withdrawal manifestations and reduce the seizure risk. This is analogous to the well-known clonidine reduction in the severity of opiate withdrawal precipitated by naltrexone. Each patient will participate in four sequential study periods: 1) the suitability evaluation period, 2) the stabilization period, 3) the detoxification period, and 4) the efficacy evaluation period. In the suitability evaluation period, patients of any gender or race with a structured interview (SCID) diagnosis of BZ dependence who meet inclusion and exclusion criteria will be admitted for 20 days to a clinical research inpatient bed at the Connecticut Mental Health Center. Patients will then undergo a pentobarbital challenge test in order to estimate the approximate level of daily BZ requirement. During the stabilization period, patients will initially be started on the BZ agonist alprazolam (ALP) in a daily dose as predicted from the pentobarbital challenge. The ALP dose will be adjusted as needed over the first three hospital days an then maintained at the same dosage over the next seven hospital days prior to detoxification. The 5 hour detoxification procedure will utilize a single administration of flumazenil (n=20) intravenously preceded by a single oral dose of the barbiturate anticonvulsant phenobarbital. A parallel control group will receive placebo (n=20) instead of flumazenil in double blind fashion. Whether flumazenil reverses BZ dependence will be assessed by twice daily measurement of BZ abstinence symptoms and signs in both groups after abrupt ALP discontinuation via single blind substitution of placebo over hospital days 11 to 20.

This is one of four independent but identical applications for a multi- center treatment study of panic disorder (PD) comprising the first study designed to assess the relative efficacy of a pharmacologic treatment, a cognitive behavioral panic control treatment and their combination for patients with PD. The study is designed as a 12 week acute treatment trial, followed by 6 months of maintenance treatment and 6 months of follow-up. PD is a prevalent chronic and debilitating disorder. Although some studies are available documenting the efficacy of both pharmacological and behavioral treatments for patients with agoraphobia, behavioral treatments for agoraphobia are very different from the newly developed cognitive behavioral treatments for PD. Preliminary studies suggest that these treatments may be quite effective. Surprisingly, few studies exist evaluating pharmacological treatments for PD without agoraphobia. Yet, a variety of evidence suggests that drugs are effective for panic attacks. It is also possible that the combination of psychological and pharmacological treatment will provide the optimal approach for many patients or that relapse rates after treatment discontinuation will differ. Central to this proposal is the collaboration of four research sties (SUNY Albany, Cornell, Hillside/Columbia and Yale) representing both psychological and pharmacological orientations. The sites will enroll a total of 600 patients over 4 years. Patients will be randomly assigned to one of five treatment cells: imipramine (IMI) with medical management, pill placebo (PLA) with medical management, Panic Control Treatment (PCT) or a combination of PCT with either IMI or PLA. In addition to establishing relative efficacy, this design will allow us to establish guidelines for treatment of PD at sites wit somewhat different orientations, identify comparative mechanisms of action of psycho-and pharmacotherapy, and introduce innovative methods to integrate medication and psychosocial treatment modalities for PD patients. An additional goal will be to examine the implication of prior psychoactive substance abuse for treatment outcome as well as the utilization of substances as coping mechanisms for anxiety and panic.

DESCRIPTION (Adapted from applicant's abstract): Psycho-pharmacologic treatments are among the most important services investigators have to offer to patients with mental illnesses. Although a relatively rich database is available about how psychotropic medications perform in rigorous placebo-controlled efficacy trials, much less is known about the extent to which specific medications improve outcomes in patients in natural treatment settings. The objective of this proposal is to take advantage of the research, service, and education capacities now available in the State of Connecticut, Department of Mental Health (DMH) and at Yale University School of Medicine (Yale) to advance the field of psychopharmacology into medications effectiveness research by creating a clinical mental health service research program focusing on the research theme of medication effectiveness -- the Medications Effectiveness Research Development Program (MERP). The MERP will be built primarily by recruitment of established and developing psychopharmacology mental health clinical researchers in the Yale University School of Medicine Department of Psychiatry (Yale) into the medications effectiveness services research field. The MERP is designed to strengthen an existing public academic liaison (PAL) between the State of Connecticut Department of Mental Health Research Division (DMH) and Yale by enhancing the services research component of the ongoing DMH-Yale collaboration. Senior outside consultants have been recruited to assist in the building of increased local expertise in clinical mental health services research, mental health economics, and biostatistical analysis. Pilot projects from program investigators will be solicited, reviewed, funded, and monitored by the program. Data from the pilot projects will then be used to demonstrate the promise and feasibility of studies proposed in subsequent independent grant applications. The MERP will focus on medications effectiveness questions across a broad range of research methodologies and psychopathologic targets. Proposed studies address questions of treatment effectiveness, implementation effectiveness, and medication utilization. Six approved studies are proposed in the psychopathologic areas of depression, anxiety, psychosis, and dual diagnosis of mental illness and substance abuse. Study 1 will investigate the treatment effectiveness of risperidone versus traditional neuroleptic for noncompliant patients with schizophrenia in a public sector acute inpatient unit. Study 2 will investigate the treatment effectiveness of lithium versus T3 augmentation in patients with refractory depression in a public sector outpatient clinic. Study 3 will investigate the treatment effectiveness of a specific serotonin reuptake inhibitor versus a secondary amine tricyclic in private practice patients with major depression. Study 4 will investigate the treatment effectiveness of buspirone versus benzodiazepines in generalized anxiety patients in a primary care clinic. Study 5 will investigate the implementation effectiveness of community reinforcement of disulfiram compliance in patients with alcoholism and schizophrenia in a second public sector outpatient clinic. The last study, (number 6) will investigate the implementation effectiveness of a clinician education program on adverse effects of typical neuroleptics.

DESCRIPTION (APPLICANT'S ABSTRACT): Recently a group of novel antipsychotic medications has become or are expected shortly to become available for the treatment of schizophrenia (risperidone, olanzapine, sertindole, quetiapine). Although their efficacy compared to placebo are established, the degree of benefit of these agents to patients in actual clinical practice relative to the older medications remains uncertain. In efficacy trials which have employed an active comparator in addition to or instead of placebo, the relative outcomes of these agents have been compared almost exclusively to a single agent, haloperidol. These data leave unanswered the question of pivotal importance to patients, families, and clinicians: how will the average patient benefit on one of the newer agents compared to the best choice among typical drugs based on each patient's individual previous treatment history and current clinical status? The relative cost of treatment associated with these agents also remains uncertain. It is often argued that the newer drugs will reduce hospitalization and other service utilization and that the reduced costs of service will offset the greater medication expense. The extent to which these cost savings are actually realized in practice, however, has not yet been demonstrated. This is a question of interest not only to patients, families, and clinicians but also to health care administrators, taxpayers, and formulary committees. The present proposal has two specific aims: to determine (1) the relative clinical outcome consequences and (2) the relative cost of treatment consequences of a decision to prescribe one of newer atypical antipsychotic medications vs traditional typical antipsychotic medications. These questions will be addressed using an effectiveness trial, a prospective clinical trial utilizing random assignment to open label alternatives. Patients randomized to atypical (n=200) or typical (n=200) medication classes will choose specific medications from within their assigned class. Benefit and cost outcomes will be assessed comprehensively over a one year follow-up. Eligible patients will be selected from among the group of patients acutely hospitalized for schizophrenic relapse in a state mental health care system.

Cocaine use continues to be a major public health problem, yet there are no proven medication treatments for cocaine abuse. Thus cocaine abuse represents an important target for medications development. Recent evidence primarily from preclinical studies suggests that medications which block L-type calcium channels or antagonize the function of the excitatory amino acid (EAA) gaged cation channels permeable to calcium are able to blunt the effects of cocaine. The proposed research investigates whether these medications have similar effects in humans. Three major studies, each evaluating study " effects on behavioral and cardiovascular responses to intranasal cocaine 120 mg/70 kg and cocaine placebo during six laboratory test sessions, are proposed. The first study will determine whether single 60 mg and 90 mg oral doses of the L- type calcium channel blocker nimodipine given 60 minutes prior to cocaine will reduce cocaine effects in human subjects. The second study will determine whether single 120 mg and 240 mg oral doses of the EAA release inhibitor lamotrigine given 120 minutes prior to cocaine will reduce cocaine effects in human subjects. The third study will determine whether subanesthetic intravenous doses of the noncompetitive NMDA type EAA antagonist ketamine administered via a bolus and infusion paradigm will reduce cocaine effects in human subjects. Cocaine will be administered 15 minutes into the 75 minute infusion. Ketamine doses will be based on preliminary data in healthy subjects and a pilot project evaluating the effects of ketamine alone in subjects with a history of cocaine abuse.

Three broad goals underlie this continuation application for a multicenter collaborative study of the treatment of panic disorder: 1) completion of the originally proposed study, comparing cognitive behavioral panic control treatment (PCT), imipramine or placebo administered double blind (MED) and the combination (COM), 2) comparison of treatment durability over 6 or 24 month maintenance with further 24 month follow-up, and 3) cross-over treatment of MBD and PCT nonresponders to the opposite treatment. It is clearly important to complete enrollment of the remaining 37% of 480 patients needed to answer key questions related to the relative efficacy of PcT, MED and COM. Study enrollment began somewhat later than we predicted because of rigorous attention to state-of-the-art assessment and quality control procedures. Careful thought about essential assessment domains appears to have been well worth the effort. Not only are the procedures we developed working well, but they have been used already by other investigators in the field and have influenced recent consensus on assessment of panic disorder. We devoted great care to training and certifying therapists and to developing extensive quality assurance procedures, essential to a cross site study. PCT adherence ratings are among the most detailed and rigorous in the field, while our procedures for MED training, certification and adherence monitoring reflect to a level of quality control rarely undertaken in psychopharmacology trials. Study of long term maintenance and follow-up is a natural and important extension of the efficacy study. With efficacy of short term treatment for panic disorder well established, there is growing recognition of the need to address durability of treatment, especially medication. Naturalistic follow-up of patients who participated in efficacy trials document continued intermittent symptoms and ongoing functional impairment even with continued naturalistic treatment, and a high rate of relapse following medication discontinuation. However, there are no prospective studies of long term outcome using rigorous, blinded assessment procedures and quality controlled maintenance treatment. There is a need to determine course and outcome during and after optimal long term maintenance treatment. A second natural extension is to examine whether nonresponders to one treatment modality will respond to the other. Although this is an obvious question, few studies to date have investigated sequential treatment strategies. Such approaches could provide considerable useful information. Our original study will provide definitive information for clinicians regarding the best choices for acute treatment of panic disorder. We now recognize that the cohort of subjects we have assembled also provide a unique opportunity to conduct the first large scale study of treatment durability and the first systematic study of effectiveness of cross-over treatment for nonresponders. Thus, we are proposing to add these aims.

DESCRIPTION (Adapted from the Applicant's Abstract): Among the drivers of the rapidly expanding use of the newer atypical antipsychotic medications (olanzapine, risperidone, quetiapine) is the claim that the atypical antipsychotic medications are associated with a lower risk for the development of tardive dyskinesia than are the older conventional drugs. Whether this claim is true is of great clinical, medicolegal, and pharmacoeconomic importance. Preclinical studies provide a credible rationale for why the newer atypical medications may have a lower risk of tardive dyskinesia than the conventionals; however, their lower risk has been addressed so far directly by only one published controlled efficacy trial and one study in the elderly. The purpose of the present application is to provide complementary data to these studies by using a naturalistic incidence study method. The current project proposes to investigate whether the incidence of persistent TD among patients taking atypical antipsychotic medications, alone or in combination with conventional medications, is lower than the incidence among patients taking conventional antipsychotics alone. In addition we will investigate other risk factors including affective disorder diagnosis associated with the incidence of TD in patients taking atypical antipsychotic medications and explore the prognosis and course of incident cases. To address these aims, a new sample of approximately 838 patients free of persistent TD will be recruited from the outpatient population of the Connecticut Mental Health Center (CMHC). These patients will be followed with biannual examinations for an average of 3.25 years. The CMHC was the site of a previous NIMH sponsored study (MH39665) that determined the incidence of new TD cases in the CMHC outpatient population from a sample identified between July 1, 1985 and December 31, 1986 and followed for up to 5 years. The existence of a previous sample at the same site provides a useful additional comparison group. Methods including sample ascertainment and TD assessment are closely modeled after the original work.

DESCRIPTION (Adapted from the Applicant's Abstract): Among the drivers of the rapidly expanding use of the newer atypical antipsychotic medications (olanzapine, risperidone, quetiapine) is the claim that the atypical antipsychotic medications are associated with a lower risk for the development of tardive dyskinesia than are the older conventional drugs. Whether this claim is true is of great clinical, medicolegal, and pharmacoeconomic importance. Preclinical studies provide a credible rationale for why the newer atypical medications may have a lower risk of tardive dyskinesia than the conventionals; however, their lower risk has been addressed so far directly by only one published controlled efficacy trial and one study in the elderly. The purpose of the present application is to provide complementary data to these studies by using a naturalistic incidence study method. The current project proposes to investigate whether the incidence of persistent TD among patients taking atypical antipsychotic medications, alone or in combination with conventional medications, is lower than the incidence among patients taking conventional antipsychotics alone. In addition we will investigate other risk factors including affective disorder diagnosis associated with the incidence of TD in patients taking atypical antipsychotic medications and explore the prognosis and course of incident cases. To address these aims, a new sample of approximately 838 patients free of persistent TD will be recruited from the outpatient population of the Connecticut Mental Health Center (CMHC). These patients will be followed with biannual examinations for an average of 3.25 years. The CMHC was the site of a previous NIMH sponsored study (MH39665) that determined the incidence of new TD cases in the CMHC outpatient population from a sample identified between July 1, 1985 and December 31, 1986 and followed for up to 5 years. The existence of a previous sample at the same site provides a useful additional comparison group. Methods including sample ascertainment and TD assessment are closely modeled after the original work.

DESCRIPTION (provided by applicant): This 3-site collaborative U01 aims to improve identification of individuals who will develop schizophrenic psychosis (including brief psychotic disorder, schizophreniform disorder, schizophrenia, or schizoaffective disorder) at the initial prodromal stage of illness, prior to the onset of the full schizophrenic syndrome. Accurate identification of schizophrenic psychosis risk offers what may be the field's best hope for developing more effective treatment strategies, including secondary prevention of this typically devastating disorder. Without sensitive and specific prodromal diagnosis strategies, intervention studies are controversial, and the results of any studies will have limited impact on clinical practice. Identification efforts to date have focused on attenuated positive symptoms, but these criteria do not consider negative symptoms that occur in the prodromal stages of psychosis and are fundamental to schizophrenia. To enhance the potential sensitivity of prodrome evaluation we have developed a modified version of the "Criteria of Prodromal Syndrome" (COPS) that retains attenuated positive symptoms, but also considers selected negative symptoms in the diagnosis of prodromal state. We propose to develop a schizophrenic psychosis risk prediction model, and our proposed risk factors are selected based on the hypothesis that schizophrenia results from a pathological neurodevelopmental process that occurs during a critical stage of forebrain development in gestation and affects the development of neurons primarily in the thalamic, prefrontal and frontal cortical, and limbic regions of the brain (thalamolimbic- cortical circuitry [TLCC]). These neurodevelopmental abnormalities are likely to be expressed premorbidly by subtle behavioral, cognitive, and structural "vulnerability markers". In most cases, these abnormalities require specific maturational processes (i.e., synaptic elimination, myelination), which occur around puberty, to unmask the vulnerability and trigger dysfunction, resulting in the development or worsening of attenuated positive and negative symptoms (clinically defining the "at risk" state), as well as diverse but specific impairments in social function, social cognition, neurocognitive function, olfaction, and motor function. We hypothesize that as connectivity of the TLCC becomes more dysfunctional, a consequence will be increased severity of measurable impairments with more domains being affected to a greater extent. Thus, the number and severity of symptomatic manifestations of TECC circuit impairment are indicators of a biologically high-risk state for schizophrenic psychosis. Furthermore, we hypothesize that these vulnerable neural circuits may be further perturbed by environmental events that typically occur during adolescence, such as stressful life events or drug abuse. Such stressors may exceed the adaptive capacity of relevant circuits producing the characteristic symptoms that signal the onset of the illness. To develop the schizophrenic psychosis risk assessment model we propose a 3-site prospective study of 180 individuals meeting modified "Criteria for Prodromal Syndrome", and 80 help-seeking control subjects who will be prospectively evaluated over 2-5 years for risk of developing schizophrenic psychosis. The collaborative team has developed leading instruments in this field and has substantial expertise in social cognition, neurocognition, developmental psychopathology, statistics and data management. Each site has provefi its ability to recruit prodromal patients in a previous collaboration.

[unreadable] DESCRIPTION (provided by applicant): Schizophrenia and other forms of psychosis affect approximately 3% of the population with a disorder that is usually chronic and disabling. The peak age of onset is between ages 18-30, occurring just as life's most productive years are beginning. Although genetic liability and abnormal brain development are known contributing factors, the etiology and pathophysiology of schizophrenia and related syndromes is largely unknown. To date, prospective observation of onset, i.e., the transition from vulnerability to disorder has not been possible because most persons at true risk cannot be identified premorbidly. This has hampered efforts at prevention. However, recent progress in risk ascertainment methodology has enabled reliable identification of help-seeking persons with pre-psychotic or "prodromal" clinical syndromes who develop psychosis within 1-2 years at rates between 20%-50%. Thus, clinical high-risk populations are now available for tracking prospectively the development and emergence of psychosis. However, because of the low incidence of schizophrenia and the heterogeneity of outcomes in clinical high-risk cases, single site studies cannot efficiently exploit the risk criteria in identifying predictors and mechanisms of psychosis. The NAPLS consortium was created to solve this problem. Eight NIMH-funded sites in North America studying prodromal patients using a common prodromal assessment instrument pooled data to create the largest sample of such persons worldwide (N=291), 35% of whom converted to psychosis after 2 years. An algorithm of baseline data was generated predicting psychosis with about 80% positive predictive power and 40% sensitivity. In this revised proposal, we describe a collaborative prospective study for which we will recruit 800 cases and 400 appropriate controls over 5 years using common, standardized clinical and neurobiological measures. The aim is to collect a sample with sufficient size and power to rigorously test elements critical to the liability for and development of psychosis in the biomarker domains of brain structure, electrophysiology, stress hormones, and genomics, and in the clinical domains of prodromal presentation and epidemiology. The revised proposal addresses reviewers' concerns, including the integration of the research plan and measures into a unifying framework. The findings will enhance our ability to identify persons at high risk for imminent psychosis, by refining predictors of conversion, and expanding our understanding of the underlying neural mechanisms. Such knowledge is critical for future efforts at early detection, intervention and prevention of psychotic disorders. PUBLIC HEALTH RELEVANCE: Preventing schizophrenia and other psychoses could relieve an enormous burden of personal and family suffering and economic losses to society. This 8-site project aims to increase our ability to identify high-risk individuals prior to onset and to pinpoint neurobiological changes that underlie the emergence of a psychotic disorder. These efforts are critical to the development of effective preventative intervention strategies for psychotic disorders. [unreadable] [unreadable] [unreadable]

Wildfires can temporarily increase runoff and erosion rates in forested watersheds by several orders of magnitude, and these accelerated runoff and erosion rates have considerable geomorphic, ecological and societal significance. Surface sealing -- the formation of a thin surface layer with a very low hydraulic conductivity -- may contribute to increases in runoff and erosion after fire either through rainsplash induced compaction and disaggregation, the clogging of soil pores by ash, or the formation of low conductivity ash crusts. However, there has been very little work on the extent to which surface sealing contributes to increased runoff and erosion after fire, the sealing mechanisms involved, or the factors that contribute to an increased potential for sealing, and surface sealing effects have not been incorporated into predictive models of post fire runoff and erosion. This project will conduct an intensive, field and lab based research study to (1) determine the extent to which surface sealing contributes to increased runoff and erosion after wildfires in the western U.S.; (2) determine the various mechanisms of surface sealing and the factors that lead to an increased probability of seal formation; and, (3) develop a predictive model of the probability of surface sealing after fires, based upon the soil and ash properties in burned areas. The research will be based on six field and lab experiments. The work will result in quantitative, process-based understanding of post-fire surface sealing and new understanding of wildfire related runoff and erosion processes.

? DESCRIPTION (provided by applicant): Schizophrenia and other psychotic disorders are serious and debilitating mental illnesses that incur substantial suffering for patients and major challenges to our health care system. The clinical high-risk (CHR) prodromal phase is the period prior to the onset of psychosis when clinical symptoms gradually emerge and function declines. The presence of a CHR syndrome in young adults is associated with heightened risk (~30%) for the later development of psychosis. The North American Prodrome Longitudinal Study (NAPLS) and other CHR studies have made substantial progress towards predicting psychosis, and in showing an accelerated reduction in prefrontal cortex (PFC) gray matter (GM) density in CHR converters from pre- to post-psychosis onset, but the mechanisms driving conversion remain elusive, partly because no studies include repeated measures prior to the onset of psychosis. In NAPLS2, we found that disrupted resting-state (rs) thalamo- cortical functional connectivity prior to psychosis predicts conversion and correlates with rate of GM decline, but we do not know if rs-dysconnectivity is progressive during the prodrome. Furthermore, in NAPLS2, plasma markers of pro-inflammatory cytokines at baseline predicted the rate of GM loss in converters; these same markers also correlated with rs-dysconnectivity. We do not yet know whether these inflammatory markers drive the changes in brain structure/function or are consequences of these changes. Similarly, higher levels of cortisol, and lower mismatch negativity predicted psychosis and the rate of PFC GM decline and were correlated with each other and with measures of rs-connectivity and cytokines. This application is a competitive renewal for a nine-site, longitudinal study aimed at identifying the brain processes underlying the progression of the clinical syndromes that characterize the psychosis prodrome. The goals are: 1) to determine the pre-onset trajectories of GM decline and disrupted resting-state brain connectivity in CHR individuals who develop psychosis using MRI, and 2) to identify inflammatory and plasticity mechanisms associated with transition to psychosis. Over a two-year period, the study will repeatedly measure these indicators, and at the same time examine changes in physiological indices of brain function, social and cognitive functioning, and symptom progression. The multi-site collaboration will follow large CHR (n= 378) and demographically matched comparison (n= 162) samples that will undergo comprehensive assessments of biological and behavioral changes. This approach will answer important questions about the origins of the brain changes that give rise to psychosis and will provide insights into likely approaches to halting or mitigatig the pathological process and advance our understanding of risk prediction, both critical steps in prevention.

PROJECT SUMMARY It has now been two decades since the clinical high risk for psychosis (CHR) criteria were first formulated in service of the goal of preventing psychotic disorders, one of the most urgent unmet clinical needs in behavioral health if not in all of medicine. As with most psychiatric patients, CHR patients benefit from psychotherapies but are also often left with important treatment needs not fully addressed. Despite the critical public health need, drug development for CHR is viewed in many quarters as risky. The most daunting obstacle may be the heterogeneity of CHR course. In Aim 1 we will deeply pheno- type 1040 CHR patients across the ProNET network of 26 international sites with multi-modal biomarkers that span brain structure-function (MRI and EEG), psychopathology and cognition, genetics, body fluid analytes, natural speech/language, and passive/ecological momentary digital phenotyping, and map these biomarkers onto a core set of clinical outcome mea- sures and trajectories over a treatment-relevant time window at eight timepoints over 24 months. Biomarkers will be collected at two timepoints to map brain-behavior trajectories. Healthy volunteers (N=260) will complete a baseline assessment to quan- tify typical variation. We will also conduct exploratory studies to assess real-time behavioral data from smartphone sensors and symptom reports from surveys; novel repetition positivity and alpha-desynchronization measures derived from standard EEG paradigms; and pilot an evaluation of excitatory/inhibitory imbalance with MR spectroscopy for glutamate, glutamine, and GABA at 7 Tesla. In Aim 2 we will partner with the NIMH-selected Data Processing, Analysis, and Coordinating Center for rapid data integration and NIMH Data Archive (NDA) uploads with the proposed informatics platform. We will implement ProNET-wide standardized and near real-time data integration with the DPACC architecture to facilitate on-site monitoring, unification of standard operating procedures, and rapid data aggregation across ProNET for seamless DPACC to NDA transfer. In Aim 3 we will test the hypothesis that data-driven variation assessed by multivariate neural, genetic, and behavioral measures within the CHR syndrome predicts individualized clinical trajectories, expanding CHR stratification for broad clinical endpoints encompassing affect, anxiety, cognition, and APS with the goal of identifying behavioral and biomarker-driven patterns that can refine the CHR syndrome and promote personalized treatment decisions. These analy- ses will yield expanded outcome stratification calculators for the CHR syndrome that can predict actionable mental health trajectories in individual patients. The stratification calculators will allow future clinical trial designers to select optimal samples for determining whether a novel compound improves the particular CHR outcome of interest and pave the way for phase-specific and safe new interventions to benefit patients and their families and communities.

Summary Research suggests that if we can identify individuals at-risk for these disorders early, we may be able to improve the course of illness and hopefully prevent illness onset all together. A first generation of studies suggest that the approach of identifying those at clinical high-risk (CHR), through the use of specialized interviews with help-seeking individuals (with attenuated psychosis symptoms) is a promising strategy for exploring mechanisms associated with illness progression, understanding etiology, and identifying new treatment targets. This work has two major limitations: 1) interview methods have limited specificity as only 15-20% of CHR individuals convert to psychosis, and 2) the expertise needed to make CHR diagnosis is only accessible in a handful of metropolitan centers, and requires extensively trained staff. Here, we aim to lay the foundation for a new approach to CHR assessment that will increase accessibility, and positive predictive value. We propose to develop a new psychosis symptom domain sensitive (PSDS) battery, prioritizing tasks that show correlations with the symptoms that define psychosis (actively tapping into psychotic disorder-specific processes, rather than to trait vulnerability signs) and relatedly, that are tied to the neurobiological systems and computational mechanisms implicated in these symptoms. To promote accessibility, we utilize inexpensive behavioral tasks that could be administered over the internet; this will set the stage for later research testing widespread screening in help-seeking as well as non-help seeking populations, that would identify those most in need of in-depth assessment. Before this can be accomplished however, it is necessary to determine which tasks are effective for predicting illness course and how this strategy compares to the first-generation prediction methods. We propose to recruit 500 CHR participants, 500 help-seeking individuals, and 500 healthy controls across 5 sites and in Aim 1, develop a PSDS battery risk calculator based on measures that prove to be most sensitive to imminent conversion. Further, the inclusion of a help-seeking comparison group is critical for translating the PSDS calculator into clinical practice, where the goal is to differentiate those at greatest risk for developing a psychotic disorder from others forms of psychopathology. In Aim 2, we will compare the sensitivity and specificity of the PSDS risk-calculator to the North American Prodromal Study (NAPLS) risk-calculator (a gold-standard first-generation tool) in the prediction of psychosis conversion over a 2 year- period. Last, in Aim 3, the study will determine if the PSDS predicts functional outcomes over the course of 2 years. Predicting diagnosis is important but being able to provide early intervention to limit the disability characteristic of psychosis is a priority. This project will answer the preliminary questions necessary for a next-generation CHR battery, tied to illness mechanisms and powered by cutting-edge computational methods, that can be used to facilitate the earliest possible detection of psychosis risk.