Neurotensin (NT) has been termed an """"""""endogenous neuroleptic"""""""" because of its behavioral and biochemical similarities to antipsychotic drugs in preclinical studies and because of its known interactions with brain dopamine (DA) neurons. This is a clinical proposal that will explore alterations in NT concentrations in patients with schizophrenia. The proposed studies will test the following hypotheses: that cerebrospinal fluid (CSF) concentrations of NT and the related peptide neuromedin N (NMN) will be decreased in drug-free patients with schizophrenia compared to normal controls; that treatment with a typical and an atypical antipsychotic drug will both increase CSF NT and NMN concentrations from pre-drug levels in patients with schizophrenia; that both treatment- induced alterations in NT and/or NMN concentrations will be related to treatment response; and that NT and/or NMN concentrations will be related to peripheral indices of DA function. These hypotheses will be tested by the following specific aims: 1) determine whether the previous finding of decreased CSF NT concentrations in drug-free patients with schizophrenia compared to age and sex-matched normal controls is a reliable and reproducible finding and whether there is also decreased CSF NMN in these patients; 2) examine whether treatment with haloperidol and clozapine increases CSF concentrations of NT or NMN from pre-drug levels in patients with schizophrenia; 3) determine whether changes in CSF NT or NMN concentrations are related to treatment response in patients receiving haloperidol or clozapine; and 4) examine whether CSF NT or NMN concentrations are related to peripheral indices of DA function in patients with schizophrenia or are related to plasma drug concentrations. The potential impact of these studies is that they will yield important information about the role of NT and NMN in schizophrenia and their response to two classes of antipsychotic drugs, which may be efficacious in different populations of patients with schizophrenia. A greater understanding of the role of NT and NMN in antipsychotic drug response may be useful in the development of lipophilic NT agonists for treatment of schizophrenia.
