Publications (2)0 Total impact
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ABSTRACT: This review will focus on the treatment and prevention of schizophrenia in children and adolescents. Neurodevelopmental theories suggest that loss of gray matter and defective synaptic function are major etiological factors in this disease. The efficacy of current antipsychotic medications has been discussed, however, these drugs produce serious side effects and may adversely affect the developing brain. We propose a novel therapeutic approach, termed neuroenhancement, that aims to promote neuronal survival and optimize neuronal function through the use of drugs. The goal is to enhance glucose metabolism in the brain, which would support higher functional activity in neurons and provide neuroprotection. Future drug development for the treatment of childhood schizophrenia should focus more on optimization of neuronal function rather than tranquilization and symptomatic relief.Expert Review of Neurotherapeutics 01/2003; 3(1):29-40.
Article: Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine[show abstract] [hide abstract]
ABSTRACT: Treatment of schizophrenics with some antipsychotic drugs has been associated with an increased incidence of hyperglycemia and new-onset type 2 diabetes. Some of these drugs also inhibit glucose transport in rat pheochromocytoma (PC12) cells. The current study was designed to examine the effects of the atypical antipsychotic drugs — risperidone, clozapine and analogs of clozapine on glucose uptake in PC12 cells. Glucose transport was measured in cells incubated with vehicle or drug over a range of concentrations (0.2–100 μM). Uptake of 3H-2-deoxyglucose was measured over 5 min and the data were normalized on the basis of total cell protein. Risperidone and clozapine inhibited glucose transport in a dose-dependent fashion with IC50’s estimated to be 35 and 20 μM, respectively. The clozapine metabolite, desmethylclozapine, was considerably more potent than the parent drug, whereas clozapine N-oxide was essentially inactive. The structural analogs of clozapine, loxapine and amoxapine, both inhibited glucose transport with amoxapine being the least potent. The ability of the drugs to inhibit glucose transport was significantly decreased by including 2-deoxyglucose (5 mM) in the uptake medium. Schild analysis of the glucose sensitivity of clozapine, loxapine and risperidone indicated that 2-deoxyglucose non-competitively antagonized the inhibitory effects of these drugs. Moreover, clozapine and fluphenazine inhibited glucose transport in the rat muscle cell line, L6. These studies suggest that the drugs may block glucose accumulation directly at the level of the glucose transporter (GLUT) protein in cells derived from both peripheral and brain tissue. Furthermore, this work may provide clues about how the antipsychotic drugs produce hyperglycemia in vivo.Brain Research.