J.K. Yao

Increased turnover of platelet phosphatidylinositol in schizophrenia

The potential role of receptor-stimulated phosphatidylinositol (PI) hydrolysis in a signal transduction mechanism has been increasingly recognized. Earlier studies have suggested a defect in alpha-adrenergic receptor function in the platelets of schizophrenic patients. Little is known, however, about the mechanisms for PI synthesis, breakdown, and regulation in schizophrenia. The present study was undertaken to investigate the metabolic turnover of inositol phospholipids and inositol phosphates by incorporation of [3H]myoinositol or [32P]orthophosphate into resting and activated platelets of normal controls and schizophrenic patients with and without neuroleptic treatment. After 5 h incubation at 37 degrees C, the majority of [3H]myoinositol was incorporated into platelet PI. Following thrombin-induced platelet activation, there was rapid formation of 3H-labeled inositol phosphates (IPs) with inositol monophosphate (IP1) being the most abundant product. The thrombin-induced formation of platelet IPs was found significantly higher in both haloperidol-stabilized and drug-free schizophrenics than in normal control subjects. When platelets were prelabeled with [32P]orthophosphates, thrombin-induced formation of phosphatidic acid (PA) was also significantly higher in haloperidol-stabilized schizophrenics than in normal controls. It is thought that thrombin-induced platelet activation is mediated through hydrolysis of polyphosphoinositides (poly-PI). The present data thus may reflect an increased signal transduction in schizophrenia, which is mediated through neuroleptic-regulated inositol phospholipid hydrolysis.

Dopamine turnover in schizophrenia before and after haloperidol withdrawal : CSF, plasma, and urine studies

The dopamine hypotheses of schizophrenia and antipsychotic drug action suggest that the dopamine metabolite homovanillic acid (HVA) should change with drug withdrawal and change in clinical state. We designed a study of cerebrospinal fluid (CSF), plasma, and urinary HVA on and off haloperidol to examine the effects of drug withdrawal. CSF and plasma HVA samples were obtained in 72 healthy schizophrenic (DSM-III-R) males (age: 36 ± 7.4 years), before and after haloperidol withdrawal, which was after 6 weeks on placebo or sooner if they met specific criteria for relapse. We collected three 24-hour urine samples in 34 of these patients. In addition, CSF HVA was obtained in 24 well-screened age-matched male normal controls. HVA was measured with high-pressure liquid chromatography (HPLC). CSF HVA decreased significantly after drug withdrawal, particularly in those who met relapse criteria; drug-free CSF HVA levels were not significantly different from those of normals. Plasma HVA increased significantly after haloperidol withdrawal in relapsing patients, but not in clinically stable patients. Urinary HVA excretion decreased after withdrawal with decreased HVA clearance. We conclude that haloperidol withdrawal had a strong effect on dopamine turnover, whereas the patient’s clinical state had only a weak central effect, without affecting total body production of HVA. Conceivably, dopamine involvement in schizophrenia reflects the failure of the homeostatic mechanisms that allow for integration of different functional brain components as needed.

Incorporation of 3H-arachidonic acid into platelet phospholipids of patients with schizophrenia

Incorporation of 3H-arachidonic acid (AA) into resting platelets was carried out in normal control subjects as well as in schizophrenic patients before and after haloperidol (HD) withdrawal. Metabolic turnover of membrane phospholipids was subsequently evaluated in prelabelled platelets at various time intervals after thrombin activation. 3H-AA was mainly incorporated into phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylinositol (PI) and phosphatidylserine (PS) of resting platelets. Very minute amounts of 3H-labelling were found in phosphatidic acid (PA). Following thrombin activation, however, substantial amounts of 3H-labelling were found in PA. Such an increase in thrombin-induced PA formation was not reduced in schizophrenic patients both receiving and not receiving HD treatment. Increased labelling has been found in platelet diacylglycerol (DAG) after thrombin activation. It is therefore not likely that a decreased DAG kinase activity contributes to the accumulation of DAG. However, the thrombin-induced PA production was temporally associated with a decreased 3H-labelling in PI, but not in PC, PS and PE. The present data taken together with our previous findings suggest that the increased production of second messengers (DAG, PA and inositol phosphates) in schizophrenia may result from an increased phospholipase C (PLC) activity in schizophrenia, because thrombin-induced platelet activation is mediated by polyphosphoinositide hydrolysis through the G-protein activation.

Methodological concerns in the study of the immune system in schizophrenia

Background. Studies of immune measures in schizophrenia have shown differences with control subjects on a number of measures. However, immune measures are often not detectable in the serum or CSF of human samples and in many studies it is not clear how this was dealt with in the analysis. Methods. CSF IL-6 was measured by ELIS A in 6l drug free male schizophrenic (DSM-IIIR) patients and 25 well-screened healthy male control subjects. Serum IL-6 was measured in 43 of the 61 patients, and in 16 control subjects. Data were analyzed with and without non-detectable values to determine if this affected the results. Results. Using a value of “0” for non-detectable values resulted in significant differences between patients and controls in plasma interleukin-6. However, if these values were treated as missing, the difference was not significant. Conclusions. The treatment of non-detectable immune measures has demonstrable effects on the analysis and interpretation of the results.

135. Correlations between RBC fatty acids and 31P MRS brain measures in schizophrenia

A key issue has been whether membrane deficits identified in peripheral cells has relevance to brain biochemistry, and whether peripheral membrane deficits parallel central membrane phospholipid metabolism in schizophrenia. To address this issue, we examined the relations between RBC polyunsaturated fatty acids (PUFAs), found to be low in schizophrenic patients, and brain membrane phospholipid metabolites from different regions of interest. Phosphomonoester (PME) and phosphodiester (PDE) were determined by the in vivo P Magnetic Resonance Spectroscopy (MRS) in 9 first-episode, drug naive schizophrenic patients and 7 normal control subjects. A significant correlation was demonstrated between RBC phospholipid PUFAs and P MRS measures of phospholipid metabolites in the combined right and left frontal lobe, but not other brain regions including caudate, occipital, parietal and temporal areas. Specifically, both total and individual PUFA (20:4, 22:5, and 22:6) were significantly (p , 0.02) and positively correlated with PME levels. A significant and positive correlation was further demonstrated when ratio of PME to PDE was served as an index to compare with RBC phospholipid PUFAs. Since the quantified PME and PDE levels reflect the freely mobile water-soluble building blocks and breakdown products of the membrane phospholipids, respectively, our preliminary data thus support the notion that decreased RBC membrane phospholipid PUFAs may reflect a decreased membrane synthesis of phospholipids in brain. Moreover, such an association appears to be regionally specific, consistent with the involvement of prefrontal cortex in the pathophysiology of schizophrenia.

Determination of salivary cortisol by non-radioisotopic immunoassay

T measurement of cortisol in saliva has received considerable attention over the past few years. In blood, cortisol is largely bound to plasma proteins, whereas saliva contains no corticosteroid-binding proteins (1). Salivary cortisol has been correlated directly with the biologically active, nonprotein-bound plasma cortisol (1–3). Under stimulation, changes in salivary cortisol may be greater in magnitude than those observed in plasma (4). In addition, the cortisol level in saliva is not affected by physiological variations in the rate of saliva production or by cigarette smoking. Thus, these and other factors have led us to believe that measurement of salivary cortisol is a valid assessment of cortisol responsivity. Such a measurement has been applied to assess neuroendocrine disturbances in patients with affective disorders (2), children at risk for a psychoactive substance use disorder (5), and patients with chronic posttraumatic stress disorder (6). Salivary cortisol concentrations are ,10% of those in plasma, therefore, the method used to assay salivary cortisol requires a sensitive, but tedious radioimmunoassay (4,7). The purpose of our present study is to test whether another nonisotopic immunoassay is suitable for salivary cortisol measurement. The dissociation-enhanced lanthanide fluoroimmunoassay (DELFIAt) is a solid phase timeresolved fluoroimmunoassay, which has been applied extensively to determine serum and urine cortisol levels. The present findings suggest that the DELFIA procedure without cortisol extraction provides a reliable, accurate, and convenient alternative to assay for salivary cortisol.

410. Reduced level of the antioxidant proteins in schizophrenia

Early work on the cognitivecorrelatesof speechdisorderfoeuscdon attentionand executivefunctions.More recent work has foeused on semantic structure, especially with tasks of semantic priming. The purposeof this studywasto examineglobalneurocognitiveandspecific verbal memorycorrelatesof multidimensional speechdisorderin 178 patientswithschizophreniaat intakeinto the SchizophreniaMHCRCof theUniversityofPennsylvania. A factorsolutionfor theindividualSAPS thoughtdisorder and SANS alogia items was constructedwith three factors:negative(theaverageof povertyof contentof speech,povertyof speech,blocking,and increasedlatencyof responseratings),disorganization(derailment,tangentiality,incoherence,illogicality),andverbosity (circumstantiality, pressureof speech,distractiblespeech).110patients had global neurocognitivemeasures for analysis. Low to moderate correlationsemergedwith a specificpattern.Negativespeechdisorder was associatedwith diffuselyimpairedneurocognitivefunction;while disorganizedspeechwas more specificallyassociatedwith abstractionflexibility(r=–O.36, p= O.0003), attention(r=–O.25, p= O.008),verbal memory (r= –0.25, p=O.007), and language function (r= –0.23, P=O.O1);and verbosity was not associated with impaired cognitive abilities.The CaliforniaVerbalLearningTest (CVLT)is a list learning task that offers measures of learning, learning strategies,and verbal memory.Disorganizedspeechwas characterizedby semanticclustering deficits(r=–O.19,p= O.04)duringlist learningthatdistinguishedit from the other two spceeh disorder dimensions.The disorganizedspeech factor,whichis mostcloselyrelatedto the classicrdconceptof thought disorder,was related to a relativelyspecificprofile of neuroeognitive impairmentand semanticclusteringdeficitsas measuredby the CVLT.