PubMed · 10556743
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R Chuong. 1999. Schizophrenia.. https://doi.org/10.1016/s1079-2104(99)70079-x
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Interest in the prodromal stage of schizophrenia-the stage directly preceding the onset of psychosis-has recently undergone a dramatic increase. To a great extent, this has resulted from the convergence of two very different research traditions. Many treatment researchers have moved from a concern with symptom control to an interest in prevention and view the prodrome as the optimal stage to begin intervention with anti-psychotics. High-risk researchers, who view the identification of accurate risk factors as necessarily preceding preventive programs, have begun to move from the premorbid to the prodromal phase as the most effective starting point. Thus, researchers in both traditions have targeted the schizophrenia prodrome as the most likely gateway to prevention. However, clashes between the two traditions in approaches, methodology and research goals have also led to considerable controversy. Such issues as how best to define the prodrome, what the actual risk for schizophrenia is among prodromal individuals, and what type of medication should be used remain largely unresolved. The Hillside Recognition and Prevention (RAP) Program has been designed to address many of these and related questions. Within a naturalistic treatment framework, the RAP program combines both high-risk and treatment research strategies. Preliminary findings from a 3-year RAP pilot study, for example, suggest that the prodrome is a developmentally complex phase of schizophrenia, that it consists of distinctly different subgroups and that novel anti-psychotics are clearly beneficial for some but not all individuals. Depending upon clinical characteristics and phase of the prodrome, anti-depressants also appear highly effective.
To delineate the differences between the structural requirements necessary for recognition at sigma-1 and sigma-2 receptors, a range of phenethyl- and phenylpropylpiperidines were evaluated in binding assays. Phenethylpiperidines were found to favor sigma-1 receptors, whereas phenylpropylpiperidines tend to favor sigma-2 receptors. It appears that phenylpropylamine is a potential pharmacophore for selective sigma-2 ligands.
A liquid chromatographic-tandem mass spectrometric (LC-MS-MS) assay was developed and validated to quantitatively determine olanzapine (OLZ) concentrations in human blood. Liquid-liquid extraction, using n-butanol:cyclohexane (3:47, v/v), was used to isolate OLZ and its internal standard, LY170158, from the biological matrix. Chromatographic resolution of OLZ from endogenous interferences and known metabolites was accomplished with a MetaChem Monochrom HPLC column (4.6 x 150 mm, d(p) 5 microm). Detection occurred using a Perkin-Elmer Sciex API III Plus triple quadrupole mass spectrometer using positive ion APCI and multiple reaction monitoring (MRM). The linear dynamic range was from 5 to 500 ng ml(-1) based on a 0.25-ml aliquot of human blood. The inter-day precision (%RSD) and accuracy (%RE) ranged from 3.65 to 10.64 and from -2.14 to 3.07, respectively. Modifications to an existing assay for the determination of OLZ in human plasma were necessary. A different structural analog was used as the internal standard due to instability observed for the original analog when using human blood as the matrix. A second modification was the addition of the anti-oxidant sodium ascorbate to inhibit degradation of OLZ in human blood, as has been noted by other investigators. Upon fortification of human blood with sodium ascorbate (final concentration, 0.33 mM), OLZ was found to be stable for at least 1 week at -70 degrees C as well as through two freeze-thaw cycles. This assay, which will be used to investigate the distribution of OLZ in human blood, grants insight into the proper sample handling conditions needed to perform valid determinations of OLZ in human blood.