Neurochemistry

IV. Neurochemistry

IV.A. M o n o a m i n e s

IV.A. Oral 1

SEROTONERGIC FUNCTION IN DRUG- NAIVE SCHIZOPHRENIA

K.M. Abel*, V. O'Keane, R.M. Murray

The Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AE UK

The serotonin hypothesis of schizophrenia was proposed in the 1950's following the observation of the 'schizophrenia-like' syndrome associated with lysergic acid abuse. Antipsychotic agents with prominent serotonin activity, such as clozapine and risperidone, have renewed interest in the role of serotonin systems in schizophrenia.

We investigated the response of drug-naive schizophrenic patients to a neuroendocrine challenge of the serotonin system. The challenge used was D-fenfluramine, a selective serotonin- releasing agent which stimulates ACTH and prolactin release, from the anterior pituitary.

Preliminary data from 10 males (age range 22-44 years), fulfilling DSM-III-R criteria for schizophrenia, and 10 controls matched for race, age, and sex are reported. Subjects fasted and received 30 mg o-fenfluramine orally at 08.30 h. Blood was sampled at 0, 60, 180, 240, and 300 min for prolactin and cortisol estimation. Peak prolactin responses were significantly increased (p < 0.05) in the schizophrenic group compared to controls.

These preliminary data contrast with previous reports of blunted responses in drug-free (2-4 weeks), chronic schizophrenic patients, and suggest enhanced serotonin neurotransmission in schizophrenia. These findings are compatible with the serotonin-antagonist properties of the new neuroleptics.

IV.A. Oral 2

CSF AMINE METABOLITES IN SCHIZOPHRENIA AND SUICIDAL BEHAVIOUR

S.J. Cooper a, C.B. Kelly a, D.J. King b

aDept of Mental Health and bDept of Therapy Pharmacy, Queen's Univ of Belfast, 97 Lisburn Road, Belfast BT9 7BL, Ireland

A link has been established between low concentrations of 5-hydroxy-indoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) and suicidal behaviour in depressive illness (Asberg

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et al., 1976 Arch. Gen. Psychiatry, 33, 1193-1197). This finding has been strengthened by follow-up of patients for up to 9 years after initial CSF collection (Traskman et al., 1981 Arch. Gen. Psychiatry, 38, 631-636). Previous reports relating CSF 5-HIAA concentrations to suicidal behaviour in schizophrenia have found contradictory results.

We collected lumbar CSF samples from 35 drug-free patients who met the Feighner criteria for schizophrenia. The concentrations of 5-HIAA, homovanillic acid (HVA) and 3-methoxy- 4-hydroxyphenylethylene glycol were determined by high- performance liquid chromatography. Five patients were lost to follow-up but 30 were followed-up for an average of 131 months (range 108-146). None successfully committed suicide but 10 made attempts.

There were no significant demographic differences between suicide attempters and non-attempters. Suicide attempters had significantly lower CSF concentrations of 5-HIAA than non- attempters (mean [SE] 6.7 [2.2] ng/ml VS 23.6 [5.6] ng/ml; p 0.05, Mann-Whitney (U). There were no significant differences for HVA or MHPG. Those making violent attempts at suicide had significantly lower concentrations of HVA than non-violent attempters but did not differ with respect to 5-HIAA or MHPG.

IV.A. Poster 62

DOPAMINE IN CATATONIA

G. Northoff, L. Demisch, B. Pflug

Dept. of Psychiatry, University of Frankfurt, Frankfurt, Germany

Catatonia is nowadays regarded as a syndrome, which can be associated with schizophrenia, besides other psychiatric, neurologic and organic illnesses. Therefore dopamine metabolites, HVA, DOPAC, and MHPG were measured in 29 patients with catatonic syndrome, 11 paranoid schizophrenics, 10 chronic schizophrenics and 17 normal subjects in plasma.

We found a significantly higher HVA in all catatonics (22,552+ 17,633) than in normals (8,024+4,084) as well as a higher HVA, though not significantly, in catatonics than in paranoid (10,491 +6,646) and chronic (11,220+9,219) schizophrenics. Differences of MHPG between all groups could not be observed. It is suggested that catatonic hyperdopaminergia might be explained by co-oceurrent nigrostriatal hypo- and mesolimbic hyperdopaminergic functions which would account for akinetic as well as psychotic symptoms in catatonia.

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IV. A . P o s t e r 63

M O N O A M I N E O X I D A S E A C T I V I T Y ( A A N D

B) A N D G L U C O S E M E T A B O L I S M I N T H E

F I B R O B L A S T S F R O M S C H I Z O P H R E N I C S

C.N. Ramchand , A.E. Gl iddon , G.P. Hemmings

Institute of Biological Psychiatry, Wellcome Building, University of Wales, Bangor LL57 2UW, UK

Several studies indicate that schizophrenics have an altered brain glucose and monoamine metabolism. It is possible that altered brain monoamine function may lead to altered glucose metabolism in the brain. Brain glucose metabolism is usually measured using PET scans with labelled substrates whereas monoamine metabolism is measured in blood, CSF or in post- mortem brains. Fibroblasts have emerged as the best system in which to study several genetically inherited diseases which avoid the contaminating effects of medication and environmen- tal factors. Moreover, fibroblast cells cultured in vitro can express several biochemical parameters which are specific to neuronal cells. Thus in this context we have studied in fibroblasts both monoamine oxidase (A and B) and glucose metabolism and platelet monoamine oxidase (B) activity. Contrary to an earlier report we found a significantly reduced MAO A in fibroblasts (14.9__+3.1 and 8.1__+ 1.02 pmoles/min/mg protein respectively in controls, n = 6 and schizophrenics, n=6; p < 0.05;). MAO B also was reduced but fell short of statistical significance (7.39+2.04 and 4.1_ 1.06 pmol/min/mg protein respectively in controls and schizophrenics). Glucose metabolism was significantly elevated in schizophrenics (253 + 23.2 and 311 + 15.7 nmoles CO2/h/mg protein respectively in controls (n= 6) and schizophrenics (n = 6); p < 0.05). We found previously platelet MAO B was not changed in either medicated (n=44) or non-medicated patients (n= 19) compared to con- trois (n=41) (15.8__+ 1.84, 15.2+ 1.7 and 15.3+ 1.93 nmol/108 platelets/h in medicated, non-medicated patients and controls respectively). These are only preliminary investigations and warrant further studies of monoamine metabolism from fibroblasts in schizophrenic patients.

IV. A. P o s t e r 64

A R E G E N D E R D I F F E R E N C E S

G E N E T I C A L L Y R E L A T E D T O

C A T E C H O L A M I N E M E T A B O L I S M I N

S C H I Z O P H R E N I A ?

J. Wei, C.N. Ramchand , G.P. Hemmings


Serum homovanillic acid (HVA) and norepinephrine (NE), serum dopamine-fl-hydroxylase (DBH), platelet monoamine oxidase (MAO), and erythrocyte catechol-O-methyltransferase

(COMT) have been measured in 86 healthy parents of schizophrenic patients and 36 normal control subjects. The test showed that serum HVA concentration was significantly higher in mothers of female patients than in mothers of male patients (p<0.05); Kruskal-Wallis analysis revealed a significant difference in erythrocyte COMT activity among the mothers of male patients, mothers of female patients and female control subjects (H= 8.7, df= 2, p < 0.02); and the Mann-Whitney test demonstrated that erythrocyte COMT activity was significantly increased in mothers of male patients as compared with female control subjects (p<0.01), but there were no significant differences in the HVA concentration and COMT activity between the fathers of male and female patients, and male control subjects. There were no significant changes in serum NE concentration, serum DBH and platelet MAO activity in these subjects. The present study suggests that catecholamine metabolism in mothers of schizophrenic patients may play a genetic role in the gender differences of schizophrenia.

IV. A. P o s t e r 65

L O W C O N C E N T R A T I O N O F S E R U M

T Y R O S I N E I N N E U R O L E P T I C - F R E E

S C H I Z O P H R E N I C S W I T H A N E A R L Y

O N S E T

J. Wei , H . X u , G . P . H e m m i n g s


The concentration of serum tyrosine, phenylalanine and tryptophan have been measured using high performance liquid chromatography with ultraviolet detection in 24 neuroleptic- free and 83 neuroleptic-treated patients with schizophrenia, and 46 healthy control subjects. Tyrosine was significantly lower in neuroleptic-free male patients with an early onset (before 20 years of age) than in those with a late onset (20 years of age and over) (t9 < 0.05), or in early-onset or late-onset neuroleptic-treated male patients (p < 0.005 for both groups), but was not significantly lower than in male healthy control subjects (p < 0.005). Analysis of variance revealed a significant difference in the ratio of tyrosine to phenylalanine among the five groups (F= 4.52, d f= 4, p < 0.005). The ratio was lowest in neuroleptic-free male patients with an early onset as compared with the others. There was a significant difference in tryptophan (p<0.005) between the early-onset male patients taking and not taking neuroleptic drugs. There were too few female subjects to determine whether there were significant changes of the three amine acids in this study. It is suggested that there may be disturbance of balance between tyrosine, phenylalanine and tryptophan in early-onset patients with schizophrenia.

IV.B. Glutamate

IV, B. P o s t e r 66

P L A S M A L E V E L S O F N I T R A T E A N D

N I T R I T E I N S C H I Z O P H R E N I C A N D

H E A L T H Y S U B J E C T S

I. Das, S.R. Hirsch, J. de Beileroche

Department of Psychiatry, Chafing Cross & Westminster Medical School, London W6 8RP, UK

Nitric oxide (NO) plays a vital role in many physiological and immunological functions. Recent work has suggested that the synthesis of nitric oxide, a neuromodulatory substance which is functionally coupled to the glutamatergic neurotransmitter system, is altered in schizophrenia. The aim of this study is to investigate the role of circulating plasma levels of NO metabolites to test the hypothesis that disturbances in brain NO metabolism may play a role in schizophrenia. Plasma samples from patients meeting DSM IIIR criteria for schizophrenia and from healthy volunteers were used for assay of NO metabolites, nitrate and nitrite. Nitrate and nitrite levels were assayed spectrophotometrically using Griess reagent after removal of plasma proteins by ZnSO 4. Our results showed a significant decrease in plasma nitrate levels but not in nitrite levels in drug naive schizophrenic patients. Neuroleptic treated patients had normal levels of nitrate in their plasma. But these results must be considered with caution as plasma nitrate levels may have different sources of origin. Preliminary data on platelet nitric oxide synthase activity which is similar to the brain enzyme being the constituent calcium/calmodulin dependent enzyme is also found lower in drug naive schizophrenic patients.

IV. B. O r a l 3

5 H T - G L U T A M A T E I N T E R A C T I O N S A N D

R E L A P S E O F S C H I Z O P H R E N I A

J.F.W. Deakin

Univ. Dept. Psychiatry, Rawnsley Bldg, M.R.L, Oxford Rd, Manchester M13 9WL, UK

This presentation will briefly report increased 5HT1A receptor density on glutamatergic elements in orbital frontal cortex (OFC) in schizophrenic post-mortem brains. The wider implications for pathogenesis will be discussed.

A fundamental distinction can be drawn between (a) hard- wired glutamatergic systems in the brain concerned with information processing in pre-ordained domains (e.g. locomotion; escape-avoidance) and (b) systems, such as 5HT projections, which bias the operations of hard-wired systems. Our evidence is that schizophrenia is a disorder in the hard-wiring of glutamatergic mechanisms of the basolateral circuit comprising OFC

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and anterior temporal lobe [1,2]. This circuit processes social information - language, facial expression and gesture. These functions are disordered in schizophrenia [3], possibly due to a genetic abnormality of frontal lobe function [4].

Deakin and Graeff [5] have argued that 5HT is released specifically by aversive events to facilitate adaptive coping behaviours. 5HT modulation of the social brain may mediate defensive social anxiety and maintain self-esteem. Life events and expressed emotion may exacerbate schizophrenia because 5HT defence mechanisms attempt to modulate dysfunctional social computations in the basolateral circuit. Pharmacological manipulation of 5HT mechanisms may offer a novel approach to preventing socially determined relapse in schizophrenia.

1. Balderson et al, this volume. 2. Roberts et al, this volume. 3. Whittaker et al, this volume. 4. Hellewell et al, this volume. 5. Deakin, J.F.W., Graeff, F.G. (1991) 5HT and Mechanisms

of Defence. J. Psychopharmacol. 5(4), 305-315.

IV. B. P o s t e r 67

A U T O R A D I O G R A P H I C S T U D Y O F

[ 3 H ] A M P A B I N D I N G I N F R O N T A L C O R T E X

I N S C H I Z O P H R E N I A

D. Longson, M.D.C. Simpson, J .F.W. Deakin

Dept of Psychiatry, MRL Manchester, UK

Glutamate has been the focus of recent studies to determine the pathophysiological basis of schizophrenia. Bilateral increases in glutamatergic activity in the orbital frontal cortex as measured by the binding of D-Aspartate have been reported [1]. Kainate and NMDA receptors were similarly increased. It was suggested that an abnormally dense glutamatergic innervation of the frontal area, possibly resulting from a failure in the process which re-models immature corticocortical projections during development, could account for the results.

We have now examined the binding of [3H]AMPA in the post-mortem brains of 13 schizophrenics and 18 controls matched for age and sex. 20 /~m sections of orbital frontal cortex were incubated with 4 #m [3H]AMPA and placed on autoradiographic film for four weeks. Computerised image analysis was used to estimate the degree of AMPA binding and to measure the thickness of the receptor dense band in the cortical grey.

ANOVA analysis of the results failed to demonstrate any changes in AMPA binding in schizophrenics compared to controls and there was no effect of diagnosis, sex, or side in an analysis of variance. These findings are consistent with recent homogenate studies [2]. It is proposed that neural elements which bear AMPA receptors are not involved in the putative frontal cortical abnormalities in schizophrenia.

1. Deakin, J.F.W. et al. 0989) J. Neurochem., 52, 1781-1786. 2. Kuramaji, A. et al. (1991) J. Neurocbem., 59, 829-837.

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IV. B. O r a l 4

R E G I O N A L L Y S P E C I F I C S U B C O R T I C A L

G L U T A M A T E R G I C D E F I C I T S I N

S C H I Z O P H R E N I A

G.P. Reynolds, A.J. Cut ts

Department of Biomedical Science, University of She~eld, She~eld SIO 2TN, UK

In the search for neurochemical correlates of the neuronal deficits being identified in the brain in schizophrenia, glutamatergic systems have attracted some interest. In spite of several reports to the contrary, we have been unable to identify an increase in glutamatergic neuronal markers in frontal cortex tissue taken post mortem from schizophrenic patients, although we have observed an asymmetric (left-sided) deficit of saturable D-aspartate binding to glutamate uptake sites in polar temporal cortex (1). In this preliminary study we also observed deficits in this measure of glutamatergic terminals in the caudate nucleus in some schizophrenic subjects. We have gone on to determine glutamate uptake site density in some further brain regions of potential relevance to the neuropathology of schizophrenia.

Saturable D-aspartate binding was determined in post mortem tissue taken bilaterally from the hippocampus, nucleus accumbens and amygdala from a series of subjects meeting research criteria for schizophrenia and a group of age-matched controls. While no significant asymmetry for any of these regions was observed in either group, the nucleus accumbens alone demonstrated a significant deficit of glutamate uptake sites in the schizophrenic subjects (mean values of 462 and 505 pmol/mg protein for left and right hemisphere respectively) below control values (705 and 708 pmol/mg protein).

Taken with the previous indication of deficits of glutamate uptake sites in the caudate nucleus, the deficit in the accumbens indicates a paucity of glutamatergic innervation of these striatal regions in schizophrenia, perhaps relating to deficit of input of frontal cortical or cingulate origin.

1. Reynolds G.P., Cutts A.J., Mason S.L. (1993) J Neurochem 61, S196.

IV. B. O r a l 5

A L T E R A T I O N S I N T H E E X P R E S S I O N O F

N I T R I C O X I D E S Y N T H A S E I N S C H I Z O P H R E N I A

L. Virgo a, J. de. Belleroche a, T. Barnes b, A. Mor t imer b, S. Hirsch a

aDepartments of Biochemistry and b Psychiatry, Charing Cross and Westminster Medical School, Fulham Palace Road, London, W6 8RF

Abnormalities in glutamate neurotransmission in schizophrenia are indicated from studies on glutamate receptors. Kainate

receptors are decreased in hippocampus and [aH]kainate binding is elevated in cortical regions. Analysis of N-methyl-o- aspartate (NMDA) receptors has not yielded a clear trend, although 3H-MK-801 binding has been shown to be elevated in cortical regions. NMDA receptors can also be approached by analysis of linked intracellular enzymes such as nitric oxide synthase (NOS) which is activated on stimulation of NMDA receptors to generate nitric oxide (NO). NO functions as a retrograde transmitter and this process has been implicated in long-term potentiation. Alterations in the distribution of the enzyme have already been reported in schizophrenia and in this study we analysed levels of NOS mRNA by in situ hybridization and provide evidence in support of these findings. These results indicate that an altered pattern of NOS mRNA expression occurs in schizophrenia which might arise from an impaired migration of neurones during development.

IV. C. Phospholipids

IV. C. O r a l 6

A C C E L E R A T E D B R E A K D O W N O F

P L A T E L E T M E M B R A N E P H O S P H O L I P I D S


W.F. Gat taz , A. Steudle, A. Maras , J. Brunner

Central Institute of Mental Health, Neurobiology Unit, P.O. Box 122120, D-68072 Mannheim, Germany

Phospholipase A 2 (PLA2) is a key enzyme in the metabolism of phospholipids. We and others (Noponen et al., 1993) reported increased serum PLA2 activity in schizophrenics as compared to healthy controls and to nonschizophrenic psychiatric patients. Moreover we found that neuroleptic treatment over 3 weeks reduced the enzyme activity to normal levels.

The breakdown of membrane phospholipids by PLA2 pro- duces highly cytotoxic compounds such as lysophosphatidylcholine (lyso-PC). In a new series of experiments we investigated the intracellular PLAz activity, the concentrations of membrane phospholipids and of lyso-PC. Drug-free schizophrenics showed in platelets increased PLA2 activity, decreased phosphatidylcholine and increased lyso-PC content, which suggest an accelerated breakdown of membrane phospholipids in schizophrenia.

To investigate the effects of PLA2 in the brain, we injected in rats bovine PLA2 intranigral. PLA2 caused a significant increase in spontaneous contralateral circling behaviour, sug- gesting a direct stimulation of ipsilateral dopaminergic neurons. These behavioural changes were inhibited by typical (haloperidol) and atypical (clozapine) neuroleptics.

Changes in membrane lipids induced by PLA2 were found to regulate receptor function and to affect directly the synthesis and release of neurotransmitters. These mechanisms are assumed to be relevant to the biology of schizophrenia.

IV. C. P o s t e r 68

A M E M B R A N E A B N O R M A L I T Y I N

S C H I Z O P H R E N I C P A T I E N T S W I T H T H E

N E G A T I V E S Y N D R O M E

D.F. H o r r o b i n a, A.I .M. Glen b

"Scotia Pharmaceuticals, Woodbridge Meadows, Guildford GU1 1BA, UK, bCraig Dunain Hospital, Inverness, UK

Essential fatty acids (EFAs) and especially arachidonic (AA) and docosahexaenoic acids (DHA) are important components of all neuronal membranes. EFAs influence transmitter release, reuptake and action. There are strong correlations between the EFA compositions of brain and of red cell membranes. In patients with well-defined positive and negative syndromes, we found that red cell EFA levels in the positive group were near normal, whereas the negative group had near normal linoleic acid but highly significantly reduced AA and DHA levels. Three centres in Scotland, Ireland and England provided samples from DSM-III schizophrenics not divided into positive and negative groups. In these samples the distributions of values for AA and DHA in red cells were clearly bimodal, with one range corresponding to the normal and the positive schizophrenic values and the other range corresponding to the negative schizophrenic values. Distributions of all EFAs in plasma in normals and in schizophrenics were unimodal. These observations cannot be explained by diet since the levels of the main dietary EFAs were normal in both plasma and red cells, nor by drugs since analysis of covariance showed no effects of drug dosage on EFA levels. The findings could help to explain some observations in schizophrenic patients such as resistance to pain and to arthritis. AA metabolites, derived from AA in cell membranes, are important in both pain and inflammation. The membrane changes noted would be expected to lead to modest changes in the functioning of several neurotransmitter systems since the behaviour of receptors is determined in part by their lipid environment. The observed abnormalities might be attributable to defective incorporation of AA and DHA into membranes by acyltransferases, or to excessive removal by either phospholipases or lipid peroxidation. The ability to define clearly a sub-group of schizophrenics on the basis of an unequivocal biochemical abnormality has many implications for research. Genetic studies, as well as clinical, psychological and physiological investigations might be productive if performed on such a defined group of patients.

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I N C R E A S E D P L A T E L E T P H O S P H O L I P A S E

A 2 A C T I V I T Y I N S C H I Z O P H R E N I C S A N D

R E D U C T I O N A F T E R N E U R O L E P T I C

T R E A T M E N T

A. Maras , A. Steudle, W.F. G a t t a z

Central Institute of Mental Health, Neurobiology Unit, P.O. Box 122120, D-68072 Mannheim, Germany

Recent investigations in membrane phospholipid metabolism indicated an accelerated breakdown of phosphatidylcholine in platelets of schizophrenics. Because of the central role of the enzyme phospholipase A2 (PLA2) in this process we examined the intracellular activity in platelets of 31 DSM-III-R, drug free schizophrenics, age and gender matched healthy controls and non-schizophrenic psychiatric patients.

PLA 2 activity was increased in schizophrenics (28.4+ 10.3 [pmol/mg/min]) as compared to healthy controls (23.8+8.3, p = 0.01) and non-schizophrenic patients (24.1 __+ 10.9, p = 0.03).

Further we determined the PLA 2 activity from 20 schizophrenics during 3 weeks neuroleptic therapy. PLA 2 activity decreased after the first two weeks, (15.3 + 5.6%, p = 0.005 and 14.6 + 6.7%, p = 0.008 respectively). In the third week we found the same amount of decrease, but a larger variation (15.0+7.3%, p = 0.06).

Our findings suggest that altered membrane phospholipid metabolism by an increased PLA2 activity is specific for schizophrenia. Recent NMR-spectroscopy studies reported on similar changes in the frontal cortex of schizophrenics. Further studies should clarify whether our findings in platelets reflect the observed results in the brain.


P L A T E L E T M E M B R A N E P H O S P H O L I P I D S


A. Steudle, A. Maras , W.F. Ga t t az

Central Institute of Mental Health, Neurobiology Unit, P.O. Box 122120, 68072 Mannheim, Germany

Disturbances in phospholipid metabolism of cellular membranes have been reported in schizophrenic patients, but results were not consistent. We recently found a marked difference in the activity of the phospholipid metabolizing enzyme phospholipase A 2 (PLAz) with significantly higher levels in plasma, serum and platelets from schizophrenic patients than in healthy controls or nonschizophrenic patients.

In this study we examined 38 DSM-III-R schizophrenic patients with age and gender matched healthy controls and 17 nonschizophrenic psychiatric patients. The examination was repeated in 24 patients after a 3-week treatment of neuroleptics.

There was a difference in lysophosphatidylcholine with sig-

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nificantly higher levels in schizophrenic patients (57.5+ 11.3 /tg/109 platelets) as compared to healthy controls (13.9+ 5.0, p < 0.01) and nonschizophrenic psychiatric patients (15.6 -I- 9.0, p < 0.02). We found a trend to decrease after 3 weeks neuroleptic treatment (p < 0.08). The ratio between lysophosphatidylcholine and phosphatidylcholine is different with higher levels in schizophrenics (1.28+0.53) as compared to healthy controls (0.20+0.06, p<0.03) and psychiatric controls (0.10+0.06, p < 0.005).

These findings suggest an accelerated breakdown of membrane phospholipids in schizophrenia. It could be hypothesized that a similar breakdown of phospholipids in neurons might result in functional abnormalities.


A L T E R A T I O N S O F P L A T E L E T F U N C T I O N


J.K. Yao, D.P. van Kam m en , J. Gurkl is and J.L. Peters

University of Pittsburgh and VA Medical Center, Pittsburgh, PA 15206, USA

The functional state of platelets and their possible impair- ment in response to various stimuli were assessed in saline- diluted citrated blood samples of normal male controls and schizophrenic patients with and without haloperidol (HD) treatment. In response to collagen, but not to arachidonic acid (AA) and ADP, platelet aggregation (changes in impedance) was significantly higher in both HD-treated and drug-free (DF) schizophrenic patients than in normal controls. Comparison of the secretion traces, however, indicated that only AA-induced ATP release was significantly lower in HD-treated schizophrenic patients than in normal controls. In response to thrombin, collagen, and AA the mean values of released ATP from DF patients were significantly (p<0.03, two-tailed paired t-tests) higher than the same individuals on HD treatment. Furthermore, there was a trend of increased ATP release (in response to thrombin or collagen) in the nonrelapsed group as compared to the relapsed group of DF schizophrenic patients. The collagen-induced platelet aggregation or dense granule secretion in DF patients were correlated significantly and negatively with psychosis ratings. Such changes in platelet function of schizophrenic patients were not correlated significantly with daily HD dose, plasma HD levels, or duration of illness.


C O R R E L A T I O N O F R B C F A T T Y A C I D

A B N O R M A L I T I E S W I T H C L I N I C A L

M E A S U R E S I N S C H I Z O P H R E N I A

J.K. Yao, D.P. van K a m m e n , J.A. Welker, J. Gurkl is

University of Pittsburgh and Vii Medical Center, Pittsburgh, PA 15206, USA

Fatty acid composition was quantitatively analyzed in red blood cell (RBC) ghost membranes of 20 male schizophrenic patients stabilized with haloperidol (5-20 mg/day) and of the same individuals after haloperidol (HD).withdrawal. The average days on medication and drug-free (DF) period were 52 and 40 days, respectively. No significant differences were demonstrated in levels of polyunsaturated fatty acids (PUFA's) between HD-treated and DF patients. Similarly, no significant differences were found between relapsed and nonrelapsed schizophrenic patients, although the mean levels of arachidonic acid (AA), total PUFA's or fatty acid unsaturation index (FAUI) were consistently higher in nonrelapsers than in relapsers. On the other hand, the decreases in FAUI were significantly (p = 0.04) correlated to the increases in psychosis rating which is consistent with our previous reported correlation between altered membrane fluidity and the severity of symptomatology. In addition, decreases in linoleic acid (not AA) was significantly (p<0.03) correlated to the increases in psychosis rating. The present results lend further support that decreased levels of RBC PUFA's in schizophrenic patients lie in an initial stage of PUFA's pathway, possibly a defective uptake of linoleic acid into RBC membranes.

IV. D. m R N A

IV. D . P o s t e r 73

I N C R E A S E D A B U N D A N C E O F 5 H T 1 A

R E C E P T O R m R N A I N S C H I Z O P H R E N I C

O R B I T A L F R O N T A L C O R T E X

D.J. Balderson, D.A. Roberts , F. Owen, J .F.W. Deakin

Univ. Dept. Physiological Sciences, Stopford Bldg, Oxford Rd, Manchester M13 9PT, UK

Increased 5HTIA receptor binding has been reported in frontal cortex in schizophrenia [1,2]. We investigated whether 5HT1A gene expression was correspondingly increased.

Post-mortem brain samples, matched for age and post- mortem delay, were obtained from controls and schizophrenics. Isolation of total RNA and cDNA synthesis were achieved using PROMEGA and PHARMACIA Kits [3]. The internal standard was 5HTIA mRNA with 100 nucleotides deleted from its central region. PCR products were electrophoresed

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through 2% agarose gels and visualised with ethidium bromide. Optical densities were determined from Polaroid 665 negatives using a Seescan image analyser and the results expressed as a percentage of the internal standard (Table 1).

There was a significant increase in receptor message in orbital gyrus in the schizophrenic group compared to controls but not in other areas. Since 5HT1A receptors may be located on glutamate cell bodies, the present finding may be related to the increased glutamate uptake sites reported in orbital frontal cortex samples from schizophrenics [4].

TABLE 1

Relative abundance of 5HT1A mRNA; means ___ S.E. % internal standard

Brain region Controls Schizophrenics p (t-test)

Polar frontal cortex 6 3 + 7 ( n = 1 8 ) 66+11(n=12) n.s. Orbital gyrus 60+5 (n= 10) 87-1-9 (n= 11) <0.02 Inferior temporal 51+7 (n=20) 52+ 10 (n= 10) n.s. gyrus Caudate nucleus 109+8 (n=18) 99+9 (n= 10) n.s.

1. Hashimoto et al. (1991) Life Sci., 48, 355-363. 2. Deakin, this volume. 3. Chirgwin et al. (1979) Biochemistry 18, 5294-5299. 4. Deakin et al. (1989) J. Neurochem., 52, 1781-1786.

IV. D . P o s t e r 74

T H E I S O L A T I O N A N D

C H A R A C T E R I S A T I O N O F c D N A s

A S S O C I A T E D W I T H S C H I Z O P H R E N I A

J. Mulcrone, R.M. M a r c h b a n k s

Department of Neuroscience, Institute of Psychiatry, London SE5 8AF, UK

In order to gain a greater knowledge of the underlying molecular events in the pathogenesis of schizophrenia, a set of control and schizophrenic frontal cortex samples matched for age, post-mortem delay times and agonal state have been analysed by differential screening techniques.

A control frontal cortex library was screened with schizophrenic frontal cortex cDNA versus control frontal cortex cDNA and 64 clones exhibiting differential expression were identified. cDNA inserts were amplified by PCR, Southern blotted and subjected to four further differential screens with cDNA derived from control and schizophrenic frontal cortex. Autoradiograms were examined by computerised scanning densitometry. Pair- wise and group analysis of the data showed that five of the cDNAs demonstrated statistically significant differential expression in the two tissue types. The differential expression pattern was greatest in the only drug-naive schizophrenic sample analysed. The cDNAs were subcloned, sequenced and identified

on the basis of nucleic acid homology with sequences present in the EMBL and GENBANK database.

All sequences were identified as being homologous to mitochondrial DNA. The abundance of one of the species identified is being examined in a larger sample set using dot-blot analysis. The results so far indicate a possible mitochondrial involvement in the molecular pathology of schizophrenia and may provide an understanding of the abnormal cerebral metabolism in schizophrenia identified by PET studies. Molecular genetic analysis is required to confirm whether altered cerebral metabolism is primary or secondary to schizophrenia.

IV. D. P o s t e r 75

D 2 R E C E P T O R m R N A I S O F O R M S I N

S C H I Z O P H R E N I C B R A I N

D.A. Roberts , D.J. Balderson, F. Owen, J .F.W. Deakin

Univ. Dept. Physiological Sciences, Stop ford Bldg, Oxford Rd, Manchester M13 9PT, UK

In view of the possible role of dopamine dysfunction in schizophrenia, we have investigated the possibility that a differential expression of the long (D2L) and short (D2S) isoforms of the dopamine D 2 receptor may be involved in the aetiology of the disease.

Post-mortem brain samples, matched for age and post- mortem delay, were obtained from control and schizophrenic patients. Isolation of total RNA and cDNA synthesis were achieved using PROMEGA and PHARMACIA Kits [1]. The internal standard was D2 mRNA with 100 nucleotides deleted from its central region. PCR products were electrophoresed through 2% agarose gels and visualised with ethidium bromide. Optical densities are expressed as a percentage of the internal standard (Table 1).

In the schizophrenics there were significant increases in the abundance of mRNA for D2S and D2L in orbital gyrus, D2S in inferior temporal gyrus and for D2L in the caudate nucleus. Although most patients had received neuroleptics, this would not explain localized changes. Since D2 receptors may be located on glutamatergic cells, the results are compatible with evidence for an abnormal excess of glutamatergic elements in OFC [21.

TABLE 1

Relative abundance of D2S and D2L mRNA (means_+S.E. % internal standard) in orbital gyrus

Isoform Controls (n) Scz (n) p (p-test)

D2S 82-t-9 (11) 115+6 (11) <0.005 D2 L 77+11 (11) 119-t-8 (11) <0.006

1. Chirgwin et al. (1979) Biochemistry, 18, 5294-5299. 2. Deakin et al. (1989) J. Neurochem., 52, 1781-1786.

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IV. D. Poster 76

DIFFERENTIAL CHANGES IN GENE EXPRESSION IN CORTICAL AREAS GIVE INSIGHT INTO FUNCTIONAL ABNORMALITIES OCCURRING IN SCHIZOPHRENIA

L. Virgo ~, J. de Belleroche ~, T. Barnes b, A. Mor t imer b, S. Hirsch b

Departments ofaBiochemistry and bpsychiatry, Charing Cross and Westminster Medical School, Fulham Palace Road, London, 14/6 8RF, UK

No consistent markers of pathology have been established yet in schizophrenia, although abnormalities in frontal and temporal structures are indicated from PET studies. We have used in situ hybridization to investigate functional changes focussing on the quantitation of cholecystokinin (CCK) mRNA, whose product has been shown to be depleted in schizophrenia. CCK mRNA and Go c(-subunit mRNA were measured in 8 schizophrenic and 8 control subjects matched for age and post mortem delay. The study revealed a marked decrease in CCK mRNA of 83% in frontal cortex and 63% in temporal cortex in schizophrenia with no change in Go ct- subunit mRNA in either region. There was no significant correlation of CCK mRNA loss with neuroleptic treatment or duration of illness.

IV. E. Brain Antibodies and Immune Dysfunction

IV. E. Poster 77

BRAIN ANTIBODIES IN SERA OF SCHIZOPHRENIC PATIENTS

A.E. Henneberg a, B. Yiiksektepeli a, M. Bauer b

a University of Ulm, Dpt. of Neurology, Prittwitzstr. 43, D-89075 Ulm, Germany; bUniversity of Berlin, Dpt. of Psychiatry, Hindenburgdamm, D-12203 Berlin, Germany

We have found before antibrain antibodies in the sera of schizophrenic patients, but not of normal age- and sex-matched controls [1]. This time we tested medicated and non-medicated psychotic patients. Besides, we compared neurotic and psychotic patients. Forty-nine patients suffering from schizophrenia, schizoaffective disorders, unipolar affective diseases or neurotic disorders were tested versus their age- and sex-matched controls in an indirect immunofluorescence assay (technique in [2]). Eight of the 25 schizophrenic patients were unmedicated. We found antibody-binding in 8 of 17 medicated and 3 of 8 non-medicated schizophrenic patients. Three of 6 patients suffering from schizoaffective disorders were positive, also 3 of

14 patients with affective disorders, but none of the 4 patients with neurosis. Three of the controls showed antibody-binding as well. We will increase the number of neurotic patients. However, the results show an antibody-binding phenomenon independent from neuroleptic treatment appearing in schizophrenic and some of the schizoaffective and affective disorder- patients, but not in neurotic patients.

This work was supported by a grant from the Theodore and Vada Stanley Foundation, Arlington, USA.

I. Henneberg, A., Ruffert, S., Henneberg, H.-J., Kornhuber, H.H. Antibodies to brain tissue in sera of schizophrenic patients - - Preliminary findings. Eur. ARch. Psychiatry Clin. Neurosci., 1993, 314-317.

2. Henneberg, A., Mayle, D.M., Kornhuber, H.H. Antibodies to brain tissue in sera of patients with chronic progressive multiple sclerosis. J. Neuroimmunol. 34, 1991, 223-227.

IV. E. Poster 78

FREQUENCY OF HLA CLASS II ALLELES AND CD4 ALLELES IN SCHIZOPHRENIA

M. De Her t ~, M. Z a m a n i G h a b a n b a s a n i b, J.J. Cassiman b, J. Peuskens ~

aUniversity Hospital St. Jozef, Leuvensesteenweg 517, B-3070 Kortenberg, Belgium; bCentre for Human Genetics, K.U.L., University of Leuven, Leuven, Belgium

A genetic contribution to the etiology of schizophrenia is acknowledged, but the precise mode of inheritance is not known. A polygenetic/multifactoral pattern of inheritance is likely. If so, association studies may help identify mutant alleles.

The frequency of HLA class II alleles on the DRB and DPBI locus were assessed in 107 schizophrenic patients (S) and 197 healthy controls. The schizophrenics met DSM III-R criteria and diagnosis was confirmed with OPCRIT. HLA Class II typing was done according to Buysse et al. [1]. CD4 was typed after PCR by its migration in a sequencing gel [2].

The results show only that for DPBI there is a lower frequency of allele 0101 (p=0.019) and that the frequency of CD4 alleles shows a significant excess of the A4 allele in schizophrenic patients (p= 0.037).

Significant differences in the distribution of certain HLA DR and certain CD4 alleles were found. Remarkable is that with the exception of the CD4 allele A4, only a lower frequency of certain alleles was found. This suggests that with exception of CD4, certain HLA class II genes do not play a major role in the predisposition for schizophrenia. The finding of reduction of certain HLA alleles should be viewed with caution due to the small sample size.

Research funded with grant from NFWO (Nationaal Fonds Wetenschappelijk Onderzoek).

1. Buysse I. et al. Tissue Antigens (1993), 41, 1-14. 2. Zamani Ghabanbasani M. et al. Submitted.

IV. E. P o s t e r 79

I N C R E A S E D S E R U M I g E I N

S C H I Z O P H R E N I C P A T I E N T S W H O

R E S P O N D E D P O O R L Y T O N E U R O L E P T I C

T R E A T M E N T

R. Ramchand, J. Wei, C.N. Ramchand, G.P. Hemmings


It has been suggested that immunological abnormalities may play a role in the pathogenesis of schizophrenia. Also, food allergies which can be mediated by altered IgE levels may be involved in the pathogenesis of schizophrenia. IL-4, one of the cytokines, is involved in human IgE synthesis and indirect evidence has indicated that IL-4 production in vivo may be associated with highly elevated serum IgE levels. Therefore total serum IgE and plasma Interleukin (IL)-4 were determined in patients with schizophrenia (26 neuroleptic-free, and 81 neuroleptic-treated), and in 46 healthy control subjects. The total serum IgE was significantly higher in the patients who responded poorly to neuroleptic treatment compared with the other four groups (F = 4.27, df= 4,148, p < 0.003). No significant changes were found in plasma IL-4 levels between any of the five groups. It is possible that raised serum IgE levels may characterise a subgroup of schizophrenia.

IV. E. P o s t e r 80

C O R R E L A T I O N S B E T W E E N

I M M U N O L O G I C A L A N D

P S Y C H O P A T H O L O G I C A L

M E A S U R E M E N T S I N P A T I E N T S W I T H

C H R O N I C S C H I Z O P H R E N I C P S Y C H O S I S

G. Wieselmann a, H. Fabisch a, G. Tilz b, G. Herzog a, K. Fabisch ~, B. Melisch ~, G. Langs ~, H.G. Zapotoczky b

Departments ofa Psychiatry and b lmmunology, University Hospital Graz, Austria

The immunological status as well as the psychopathology of 88 patients (59 inpatients and 29 outpatients) were evaluated. Using the criteria of DSM-III-R, the patients' diagnoses included the disorganized type, catatonic type, paranoid type and undifferentiated type of chronic schizophrenia. All patients were treated with neuroleptics and tranquillizers.

From the immunological point of view it was of particular interest to examine the humoral activation, the cellular activity and the polyclonal activation. Therefore gamma-globulin- synthesis, autoantibodies to nuclear factors, ds-DNA as well as immune-complexes and complement levels C3/C4 were investigated. All measurements could be quantitated by nephelome- try and indirect immunofluorescence. The psychopathological

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status of all patients was evaluated by BPRS, analyzing the five subscores and the total score.

The highest incidence of immunological alterations could be seen in immune-complexes, interleucin-2-receptors and gamma- globulin synthesis, but no relationship could be found between psychopathology and immunological status comparing inpatients to outpatients.

IV. F. Cytokines, Interleukins and Mediators

IV. F. P o s t e r 81

P O L Y A M I N E M E T A B O L I S M I N C U L T U R E D

F I B R O B L A S T S F R O M S C H I Z O P H R E N I C

A N D H E A L T H Y S U B J E C T S

I. Das a, C.N. Ramchand b, A. Gliddon b, S.R. Hirsch a

aDepartment of Psychiatry, Charing Cross and Westminster Medical School, London 1416 8RP, UK and blnstitute of Biological Psychiatry, Science Site University of Wales, Bangor, LL57 2UW, UK

Polyamines putrescine, spermine and spermidine have a major role in the regulation of cell growth, differentiation, metabolic pathways and on the membrane functions in mam- malian systems. Recently, polyamines have been shown to be involved in the pathophysiology of schizophrenia. In view of these studies we have measured polyamine levels in cultured skin fibroblasts from schizophrenic patients and control subjects. There was a significant increase in the levels of spermidine and total polyamines in the fibroblasts and spermine in the culture medium from schizophrenic patients. But it is not known whether these changes are associated with drug treatment as all the patients in the present study are on a variety of neuroleptic drugs. In an earlier study it has been found that patients on neuroleptic medications have significantly elevated levels of blood polyamines compared to controls. In the present study we have also found that fibroblast culture after treatment with neuroleptics showed a dose dependent increase in polyamine levels. But these results must be considered with caution as it has previously been shown that increased production of inositol phosphates, a second messenger involved in polyamine metabolism, in platelets obtained from previously medicated drug-free patients continued several months after the drug treatments had been discontinued. This preliminary report suggests that polyamines may play an important role in several membrane abnormalities in schizophrenia and warrants further investigation.

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IV. F. O r a l 8

A C L I N I C A L A N D B I O C H E M I C A L M O D E L

O F R E L A P S E P R E D I C T I O N I N

S C H I Z O P H R E N I A : A R O L E F O R C S F

I N T E R L E U K I N 2?

D.P. van Kammen , C. McAllister, J.K. Yao, M.E. Kelley, M.W. Gilber tson, J.A. Gurklis , J.L. Peters

Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

The purpose of this study was to develop a multivariate model based upon our previous studies to identify which haloperidol treated schizophrenic patients are likely to relapse following neuroleptic withdrawal. Clinical and CSF variables were obtained in 79 male DSM-IIIR chronic schizophrenic patients on haloperidol maintenance treatment. Those variables were used in a logistic regression model to identify those who relapsed (n = 45) within 6 weeks following placebo substitution from those who did not (n = 34). The oral dose of haloperidol, paranoia subscale and anxiety ratings of the Brief Psychiatric Rating Scale, and CSF interleukin 2-like immunoreactivity (IL- 2-LI) produced a model that identified correctly 80.0 percent of the relapsers (sensitivity) and 67.7 percent of the nonrelapsers (specificity) (model Z2= 19.42, p=0.0006). Relative increases in CSF IL-2-LI levels during chronic dopamine blockade may be an episode marker and may predict relapse within 6 weeks following haloperidol withdrawal in schizophrenia.

IV. F. O r a l 9

D E C R E A S E D M I T O G E N - S T I M U L A T E D I L - 2

P R O D U C T I O N I N F I R S T E P I S O D E D R U G -

N A I V E S C H I Z O P H R E N I C P A T I E N T S

R. Gangul i , Z.W. Yang, K.N.R. Chengappa , J.S. Brar, G. Shurin, B.S. Rab in

University of Pittsburgh Medical School, Western Psychiatric Institute & Clinic, Pittsburgh, PA, 15213, USA

We measured phytohemagglutinin-stimulated interleukin- 2(IL-2) production by lymphocytes in 33 drug-naive patients experiencing their first episode of RDC schizophrenia or schizoaffective disorder, mainly schizophrenic, as compared to 33 age, race and gender matched controls, using a newly developed ELISA kit (R & D Systems, Minneapolis, MN). We also screened for antibodies to ANA, mitochondria, smooth muscle, gastric parietal cell, thyroglobulin and thyroid antigens using conventional serological methods. We determined age of onset (AOO) by interviewing patients and reliable informants, for the earliest appearance of morbid dysfunction.

The mean IL-2 production within patients was significantly lower than in control subjects (p < 0.005). Patients with positive

titers for one or more of the autoantibodies had significantly lower IL-2 production values than autoantibody-negative patients (p < 0.003). There was a positive correlation between IL-2 production and AOO (r = 0.47, p = 0.006).

These results confirm earlier reports (by us and others) of decreased IL-2 production in schizophrenic patients. The association with circulating autoantibodies suggests that this abnormality may be related to autoimmune phenomena, and the absence of prior drug treatment in these patients indicates that this is not a drug effect. The correlation between low IL-2 and early AOO may reflect a more severe form of illness in these subjects.

IV. F. O r a l 7

I N T E R L E U K I N - 2 ( IL-2) A N D

I N T E R L E U K I N - 2 R E C E P T O R ( I L - 2 r )

P R O D U C T I O N I N S C H I Z O P H R E N I A

M.D. O 'Donne lP , S.V. Cat ts a, P.B. Ward ~, D. Wakefield b, B. Liebert ~, N. M c C o n a g h y ~

Schools ofaPsychiatry andbpathology, University of New South Wales, Prince of Wales Hospital, High St, Randwick, NSW 2031, Australia

Studies of both cellular and humoral immunity in patients with schizophrenia are suggestive of immune dysfunction but the significance of these findings remains unclear. More recent studies have attempted to identify levels of specific cytokines in schizophrenic patients to determine any parallels between schizophrenia and autoimmune diseases. Decreased IL-2 production upon mitogen stimulation is frequently found in autoimmune diseases and recent studies have demonstrated decreased IL-2 production in never-medicated patients with schizophrenia and in medicated patients during the acute phase of their illness. Increased soluble IL-2 receptors have also been demonstrated in the serum of medicated patients in two studies but these findings require further replication. In the present study we measured production of IL-2 and IL-2r by lymphocytes stimulated with PHA in 13 unmedicated patients, 13 medicated patients and 13 age-sex matched controls. Patients were diagnosed according to DSM-III-R, and rated on the SAPS, SANS, and BPRS. In contrast to previous findings we found significantly elevated IL-2 production in unmedicated patients compared with medicated patients and controls but no differences in IL-2r production. The relevance of these conflicting findings will be discussed in relation to clinical data and in light of increasing evidence concerning a neuromodulatory role for cytokines.

IV.F. Poster 82

EXPRESSION OF S E R U M S I A L Y L T R A N S F E R A S E S C H I Z O P H R E N I A

IN

R.K. Shelley a, C.M. Regan b, E. O'Driscol l b

aSt John of God Hospital, Stillorgan, Co Dublin, Ireland, bDept of Pharmacology, UCD, Belfield, Dublin 4, Ireland

Introduction. Developmentally regulated neural cell adhesion molecules (NCAM) are important in CNS morphogenesis. Its regulatory functions are mediated by its sialylic acid content. The modulating enzyme is sialyltransferase. Abnormal modulation, and thus cell development, can generate altered neural plasticity or hyperinnervation, suggested to be aetiological factors in schizophrenia. We have previously demonstrated an increased expression of NCAM in serum of patients with schizophrenia. The activity of sialyltransferase in schizophrenia is being investigated.

Methodology. Schizophrenic patients who met DSM-III-R criteria and who comprised two groups: (i) chronic depot clinic attenders (n=13), and (ii) hospitalised, neuroleptic naive patients (n = 5), were venipunctured. Activity of sialyltransferase was expressed as nmoles of [14C]sialic acid transferred per mg protein. Results were compared with age-matched con- trois (n=21).

Results. Sialyltransferase activity in controls is 6.2 (+0.3) nmol/mg prot., in schizophrenics 7.5 (+0.2)nmol/mg prot., and in neuroleptic naive patients 8.5 (+0.6) nmol/mg prot. Unpaired Students t-test shows significant differences between both schizophrenic groups and controls, but not between the two schizophrenic groups.

Discussion. Findings are in keeping with reported elevated expression of NCAM in schizophrenia. They support the hypothesis of altered neural plasticity contributing to impaired CNS structuring in schizophrenia. This seems developmentally mediated.

IV. G. N e u r o e n d o c r i n e

IV. G. Poster 83

GONADOTROPHIN RESPONSE TO NALOXONE CHALLENGE IN MALE AND FEMALE PSYCHOTIC PATIENTS

J. Kulkarni , D. Smith, D. McKenzie , C. Hill, N. Keks, B. Singh, D. Copo lov

The Mental Health Research Institute of Victoria, Cnr Oak & Park Streets, Parkville, Vic. 3052, Australia

Although gender differences in psychosis have been well described, few neuroendocrine studies measuring sex hormones

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have been conducted to date. We measured gonadotrophin release in response to naloxone challenge in 10 female and 11 male neuroleptic-free, physically well, psychotic patients and compared them with age, sex and menstrual cycle phase matched controls. All females were pre-menopausal and con- traceptive-free. Six 10 ml blood samples were taken at 20 min intervals via a peripheral intravenous cannula. Two baseline samples were taken, followed by administration of 10mg intravenous naloxone over 5 min. Radioimmunoassays of luteinizing, follicle-stimulating hormones (LH, FSH), estrogen, progesterone and testosterone were performed. Significant differences were found between female patients and controls but not in the male group. Female patients had higher baseline LH levels compared with female controls (p=0.048). Female patients showed greater response to naloxone challenge as shown by the greater area under LH curve (p=0.047). This difference was most significant in the luteal phase. There were no significant differences in FSH response, baseline estrogen, progesterone, testosterone. Overall, the psychotic female group demonstrated hypergonadotrophinism compared with female controls.

IV. G. Poster 84

NEUROENDOCRINE TEST OF CHOLINERGIC FUNCTION IN SCHIZOPHRENIA

V. O 'Keane , K. Abel, R.M. M u r r a y

King's College School of Medicine & Dentistry and the Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AE UK

The hypothesis that increased central cholinergic neurotransmitter function may be present in schizophrenic illness and may underlie negative symptoms was tested using a neuroendocrine challenge approach. The cholinergic challenge used was the anticholinesterase pyridostigmine, thought to cause the release of growth hormone (GH) from the anterior pituitary by diminishing inhibitory somatostatin tone. Eleven patients, 6 drug-naive and 5 drug-free, satisfying DSM 11 I-R criteria for schizophrenia, and 11 matched controls took part. Subjects received pyridostigmine (120 mg orally) and blood was sampled at 0, 60, 90, 120 and 180 min for GH estimation. Peak GH responses were significantly increased in the schizophrenic group compared to controls. There was no relationship between individual peak GH values and negative symptom ratings (Scale for the Assessment of Negative Symptoms). Neither could a relationship be established between overall psychopathology or dyskinesias and GH responses. This study suggests that schizophrenia may be associated with increased cholinergic neurotransmitter function but the relationship of cholinergic dysfunction to the psychopathology of schizophrenia may be more complex than previously considered.

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IV. G . P o s t e r 85

H I G H C O N C E N T R A T I O N S O F P L A S M A

A L D O S T E R O N E A N D N O C H A N G E O F

S E R U M H V A I N N E U R O L E P T I C - F R E E

M A L E P A T I E N T S W I T H A N E A R L Y - A G E

O N S E T O F S C H I Z O P H R E N I A

C.N. R a m c h a n d , R. Ramchand , J. Wei, J.L.P. Davies, G.P. Hemmings

Institute of Biological Psychiatry, Wellcome Bulding, University of Wales, Bangor LL57 2UW, UK

Polydipsia occurs frequently in mentally ill patients. Although neuroleptics and lithium may contribute to polydipsia by directly stimulating hypothalamic thirst centres, about 25 per cent of chronic schizophrenic patients have excessive water intake of unknown etiology. It was decided to examine aldosterone as it regulates the water-salt balance and also the relationship between homovanillic acid and aldosterone as dopamine affects the renin-angiotensin-aldosterone system. Plasma aldosterone, serum sodium and homovanillic acid (HVA) were measured in male early age ( < 19 years) and late age (> 20 years) onset schizophrenic patients with or without neuroleptic treatment, and in male healthy control subjects. Kruskal-Wallis analysis revealed a significant difference in plasma aldosterone among the five groups (H= 15.4, df--4, p<0.005): neuroleptic free patients with an early-onset age (n = 10), neuroleptic-free patients with a late-onset age (n = 10), neuroleptic-treated patients with an early-onset age (n = 14), neuroleptic-treated patients with a late-onset age (n = 27), and healthy control subjects (n= 18). The Mann-Whitney U-test showed that the concentration of plasma aldosterone was significantly higher in both the neuroleptic-free and neuroleptic- treated groups in the patients with an early age of onset than in healthy control subjects (p < 0.02 and p < 0.001, respectively). In the neuroleptic-treated group, significant differences were not found in plasma aldosterone between patients with a late onset and healthy control subjects (p < 0.007). Such differences were found in the neuroleptic-free group. Also, significant differences were found in serum HVA between patients with early-onset-age and late-onset-age (p < 0.05) in the neuroleptic treated group. No significant changes were found in serum sodium and HVA between the five groups. The present study suggests that increased aldosterone with no change in HVA may constitute a different sub-group and may serve as a biological marker in schizophrenia.

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