Herbert Y. Meltzer, M.D. - US grants

(Adapted from the applicant's abstract) Dr. Meltzer is applying for renewal of his renewal of his RSA to further study the roles of 5-HT, dopamine (DA) and their interaction in SCH, MD, and OCD, as well as in the mechanism of action of various psychotropic drugs, especially clozapine (CLZ) and other atypical antipsychotic drugs (APD). Pursuant to these goals, 14 study aims are proposed. These are: (1) to test whether melperone (MEL) is a effective as CLZ in treatment-resistant SCH; (2) to test whether amperozide (AMP) is an effective atypical APD; (3) to test the hypothesis that the 5-HT2-D-2 antagonist ratio can contribute to the identification of atypical APD's; (4) to validate buspirone in man as a 5- HT1a probe by testing the ability of pindolol, a 5-HT1ald antagonist to block the buspirone-induced increases in plasma prolactin (PRL) and cortisol; (5) to validate MK-212 in man as a 5-HT2 probe by determining if its effects on plasma PRL, adrenocortiotropic hormone (ACTH) and cortisol can be inhibited by pretreatment with ritanserin, a 5-HT2 antagonist, but not by pindolol; (6) to validate 5-HTP in man as a specific 5-HT2 probe by demonstrating that the effect on 5-HTP, ACTH and cortisol secretion is not blocked by treatment with pinodol as it is by retanserin; (7) to test the hypothesis that ACTH, cortisol, and prolactin responses to buspirone and MK-212 are blunted in patients with SCH; (8) to test the hypothesis that ACTH, cortisol or PRL responses to 5-HTP or MK-212 in SCH are inhibited by treatment with clinically effective doses of MEL and AMP as it is by CLZ; (9) to demonstrate that atypical APD's other than CLZ decrease basal plasma ACTH, cortisol and 24 hour urinary free cortisol and increase lymphocyte glucocorticoid receptor binding sites; (10) to test the hypothesis that APD's other than CLZ will increase 5-HT2 platelet binding sites and this increase will be proportional to their efficacy; (11) to test the hypothesis that atypical APD's occupy brain D2 and 5-HT2 sites through imaging studies; (12) to test the hypothesis that atypical APD's increase 5-HT release in rat striatum and accumbens and do not increase D2 release; (13) to test the hypothesis that there is elevated 5-HT2 and 5- HT1a binding sites in suicide brains after assessing both violence and diagnosis by psychological autopsy; and (14) to test the hypothesis that specific 5-HT uptake blockers enhance the response to MK 212 and 5-HTP but not mCPP in both OCD patients and controls. The human studies involve neuroleptic resistant and neuroleptic responsive patients with schizophrenia recruited from four different Clinical Research Centers, which admit over 100 such patients and treat 30 patients per year on an out-patient basis, as well as normal volunteers. These subjects and/or patients will be recruited from the applicant's hospital and paid for their participation. Informed consent will be obtained and blood samples will be drawn. The animal studies involve about 2,300 Sprague-Dawley rats per year for dialysis and endocrine challenge experiments.

This is an application for a Specialized Mature Mental Health Center (SMH- CRC). The major theme of the SMH-CRC is the longitudinal study of the pathophysiology and somatic treatments of schizophrenia and mood disorders integrated with informative preclinical research. The major aims of the preclinical research are to investigate the mechanism of action of antipsychotic and thymoleptic drugs and animal models of schizophrenia and mood disorder. The SMH-CRC resources provide infrastructure support to ten core laboratories which facilitate the research of multiple SMH-CRC Investigators. These cores and their major functions are: 1) the Diagnosis and Assessment Core, the functions of which are: a) to recruit schizophrenic and mood disorder patients, related clinical populations and normal controls for participation in multiple, related protocols; b)to provide accurate, standardized diagnosis and assessment of psychopathology over the short and long term; and c) to carry out research or nosology and psychopathology; 2) the Data Management, Analysis and Research Design Core which provides: a) consultation on research design; b) data management and audit; c) a central data bank; and, d) data analysis; 3) the Psychopharmacology Core, which supports and coordinates treatment studies in: a) schizophrenia, especially the effect of clozapine, other atypical antipsychotic drugs, and ECT; and b) studies of drug therapy of mood and related personality disorders (borderline personality disorder, OD); 4) the Neuroendocrinology Core, which supports challenge studies with serotonin (5-HT- and dopamine (DA)-related drugs in schizophrenia, mood disorders, related disorders and normal volunteers; 5) the Neurochemistry Core, which supports post-mortem plasma and CSF neurochemical studies of serotonergic and dopaminergic neurotransmission in schizophrenia, mood disorders and suicide as well as drug plasma level studies; 6) the Brain Imaging Core, which provides; a) CT and MRI measures of brain structure, and b) PET studies of the serotonergic and dopaminergic systems and regional metabolism in schizophrenia and depression; 7) the Neuropsychology Core, which provide measures of cognitive, especially memory, function in schizophrenia; 8) the Psychophysiology Core, which supports eye tracking, motion perception and backward masking studies in schizophrenia and mood disorders; 9) the Neuroscience of Schizophrenia/Antipsychotic Drug Core which supports basic research on the mechanism of action f typical and atypical antipsychotic drugs and animal models of the pathophysiology of schizophrenia, e.g. effect of chronic antipsychotic drugs on neurotransmitters, role of glucocorticoids in neurotoxicity; and 10) the Neuroscience of Mood Disorders/Mood-Drug Core which supports research on the regulation of HPA axis in rodents to determine the basis for HPA abnormalities in major depression and basic studies on the mechanism of action of antidepressants. The SMH-CRC also provides pilot funds for Investigations and has facilitated the training and career development of a large cadre of young investigators.

Examine the functional response of 5HT1a in unmediated psychiatric patients by examining hormone responses following the oral administation of ipsapirone. Also, determine the hormone effects of ipsapirone are modified by chronic treatment with antidepressants, lithium carbonate of antipsychotic drugs. We are still in the begining stages of the study thus, recruit is essential at this time.