Jeffrey Lieberman, M.D. - US grants

The applicant has been the recipient of an RSDA levels I and II from 1985 through 1995. During this period he has trained and conducted studies in the psychobiology and psychopharmacology of schizophrenia. This application is for a five year renewal of the RSDA level II award to enable the applicant to extend his work in the psychobiology of schizophrenia and acquire additional expertise in functional neuroimaging and neurobiology. In the last five years the applicant has successfully carried out a Prospective Study of Psychobiology in First Episode Schizophrenia that has characterized the clinical and biological course of the early stages of the illness and identified measures of prognosis and illness subtypes. These results have been widely presented and published in the scientific literature. He has also conducted a series of pilot studies addressing specific findings of the core project including the demonstration of antipsychotic drug effects on striatal morphology; and brain structure function relationships using event related potentials and MRI. In the next funding period the applicant plans to extend these lines of investigation by conducting a series of six projects. These include D.1) Prospective study of psychobiology and atypical antipsychotic treatment outcome in first episode schizophrenia- ascertainment of a new cohort; D.2) Prospective study of psychobiology in schizophrenia - long-term follow-up of the original cohort; D.3) The acute and long-term efficacy of clozapine in drug naive first episode schizophrenia in China; a randomized double-- blind comparison to chlorpromazine; D.4) In-vivo PET study of presynaptic and extracellular dopamine in drug naive first episode schizophrenia; D.5) Sensitization mechanisms in the pathophysiology of schizophrenia; D.60 Antipsychotic drug effects on basal ganglia morphology. The overarching hypothesis of this work is that the pathophysiology of schizophrenia involves a neurodegenerative process which can be characterized and treatment of which will prevent the deterioration and chronic morbidity of the illness.

Based at the University of North Carolina, this MHCRC is a multidisciplinary organization of scientists and support staff that includes important collaborators in other Departments and Centers intra and extramurally. The UNC-MHCRC supports studies of the Neuroscience of Mental and Behavioral Disorders focusing on the neurobiological bases and treatment of mood and psychotic disorders, and the psychopathological and physiological effects of stress. The aims of the MHCRC are 1) to generate and test hypotheses in thematic areas of interest; 2) to foster the integration of basic and clinical research; 3) to train young investigators within the research infrastructure of the MHCRC; and 40 to enhance faculty development and productivity by the coordination and facilitation of thematically linked research within the MHCRC's community of investigators. While this MHCRC began 17 years ago as a compendium of related projects focusing on psychoneuroendocrinology, it has matured into a core based center whose goal is to provide the infrastructure (both physical and intellectual) to facilitate state of the art thematically integrated neuroscience research in a cost-effective manner. The health and dynamic nature of the MHCRC are reflected in the sustained evolution of the cores as its investigators' scientific interests and needs have developed. The MHCRC has 7 core units: 1) Administrative; 2) Clinical Assessment and Procedures; 3) Behavioral and Cognitive Neuroscience; 4) Neuro-imaging; 5) Analytical and Applied Neuroscience; 6) Data Management and Biostatistics; and 7) Information Technology. Through the functions of its cores and programs, the MHCRC focuses research around 4 themes: 1) neurobiology of mood disorders; 2) pathophysiology of stress transduction in mental and medical disorders; 3) neurobiology of psychotic disorders; and 4) psychopharmacology. The MHCRC continues its interest in children, as well as adults, across all themes, and supports research projects that focus on understanding the roles of both gender and race in mental health. A particular strength of this MHCRC is the close interaction of basic and clinical neuroscientists enabling translation of basic research findings into clinical investigations. The organizational structure and program of the MHCRC provide for the efficient operation and interaction of the cores, dissemination of information between investigators and across projects, the maintenance of rigorous methodologic and ethical standards, and quality control of the supported research. The importance of strong leadership of the MHCRC to achieve these ends was recognized by the recruitment during the last funding period of Jeffrey A. Lieberman to succeed Arthur J. Pranger, Jr., the founding Director of the UNC-MHCRC. Dr. Lieberman's research interests and experience provide the ideal complement to the MHCRC at this point in its development. Together, Drs. Prange and Lieberman have led MHCRC scientists in developing a research plan for the next funding period that combines historical continuity with a vision of the scientific future.

risperidone; human therapy evaluation; psychosis; mental disorder chemotherapy; haloperidol; adolescence (12-20); serotonin inhibitor; child mental disorders; drug screening /evaluation; antipsychotic agents; clinical research; human subject;

DESCRIPTION (Adapted from the Applicant?s Abstract): Objectives: This is one of four identical revised applications of a collaborative R01 proposal being conducted at the University of Washington, Seattle, WA, University of North Carolina (UNC), Chapel Hill, NC, Harvard Medical School, Boston, MA and Case Western University, Cleveland, Ohio. The study will examine the long-term effectiveness of three different antipsychotic medications in the treatment of early onset schizophrenia and schizoaffective disorder: risperidone (RIS), olanzapine (OLA), the molindone (MOL) over a one year period. Specific Aims: 1) To determine the efficacy of MOL, RIS, and OLA in reducing psychotic symptoms in youth with schizophrenia and related disorders; 2) To determine the ability to sustain treatment over one year with each of these agents; 3) To examine the effects of treatment on adaptive and neurocognitive functioning; and 4) To examine the safety and tolerability of these agents in the pediatric population, particularly potential effects on neuropyramidal symptoms and weight gain. Research Design: 168 youths (ages 8-19 years) with schizophrenia, schizophreniform disorder or schizoaffective disorder and active psychotic symptoms will be recruited across four sites. Subjects will be randomly assigned to double-blind treatment with one of the three study medications. Standard dosage schedules will be followed, with modifications allowed dependent on the clinical status of subjects. Antipsychotic agents will be cross-tapered over the first week of the study to prevent exacerbation of psychotic symptoms. Symptom ratings and neurocognitive testing will be performed at baseline and repeated at specific intervals. The acute phase of treatment will last 8 weeks. Subjects with clinically significant improvement and without intolerable side effects, will continue maintenance therapy for an additional 44 weeks. Tolerance of the study medications will be systematically monitored with assessments for extrapyramidal side effects and weight gain. Revision of treatment algorithms, reliability testing and data analysis will be coordinated between the four sites. Randomization, preparation of study medications, and overall management of the database will be centralized at UNC. Revisions: To address reviewers concerns, the revised proposal has added a fourth site (Harvard), revised the data management and analysis plan, and adjusted some of the primary outcome measures. Significance: There are very few controlled studies to inform clinical practice for the treatment of youth with psychotic disorders. This study will provide information about the comparative effectiveness of the most commonly used and representative antipsychotic drugs in youth with schizophrenia spectrum disorders.

DESCRIPTION: (Verbatim from the Applicant's Abstract) We have hypothesized that the clinical deterioration observed in the early stage of schizophrenia is due to a process of limited neurodegeneration that begins in the prodromal phase and is associated with the persistence of positive and negative symptoms. In our prior study we have demonstrated the clinical progression of the illness in first episode patients over a four-year period. Preliminary volumetric MRI data from that study and from several other groups support this hypothesis but are inconsistent and inconclusive. Moreover, despite the numerous cross-sectional 'H-MRS studies of decreased NAA in temporal and frontal cortices in schizophrenia, there have been no longitudinal 'H-MRS studies. Therefore, the proposed study will utilize high resolution magnetic resonance imaging, combining MRJ and MRS in a longitudinal study with repeated measurements to determine whether the clinical progression seen in patients will be reflected by changes in brain morphology and NAA. Specifically, we predict that the progression of brain pathology seen in changes in MRI and MRS measures between baseline and end point assessments (decreasing volumes of cortical gray matter, decreasing hippocampus, increasing lateral and third ventricles and increasing subarachnoid space and decreasing lH-NAA in mesiotemporal and prefrontal cortical regions and thalamic nuclei) will be observed in a subgroup of patients with poor clinical outcomes reflected by recurrent or persistent psychopathology and functional impairment and who exhibit the greatest clinical deterioration during the scanning intervals. We also will examine trealment effects in terms of whether it prevents pathological progression in patients or introduces artifactual effects (such as in the basal ganglia). Finally, we will determine whether there are structural or metabolic abnormalities that are present at the first episode of schizophrenia which predict long-term clinical outcome. We hypothesize that MRI measures of more severe brain pathology at study entry (as reflected by greater lateral and third ventricles volumes, reduced cortical gray matter, and reduced NAA concentration in the frontal and mesiotemporal lobes and the thalamic nuclei) will be associated with poorer long term treatment outcome. We also hypothesize that treatment will be associated with preservation of brain volume in these brain regions and preservation or enhancement of NAA concentration in the frontal and temporal lobes. To test our hypotheses we will prospectively examine 100 patients ascertained in their first episode of schizophrenia using high resolution MR and spectroscopic imaging over a three-year period. Treatment will be standardized using an open label clinical treatment algorithm that provides optimal treatment with atypical antipsychotic drugs. Patients will be assessed for psychopathology, social and work performance and with MRI and MRS at study entry and at six months, eighteen months and three year of follow-up. MRI data will be analyzed using segmentation methods to determine the volume of specific regions of interest. NAA will be determined by quantitation of NAA, Cr and NAAJCr. This study will provide important information about the clinical and neuropathological course of subgroups of schizophrenia and therapeutic strategies for early identification and intervention.

schizophrenia; behavioral genetics; psychobiology; clinical research; human subject;