225. Volumetric magnetic resonance imaging in twins concordant and discordant for schizophrenia

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prefrontal function, as assessed by working memory tasks in schizophrenia patients. Working memory deficits are present in about 80% of schizophrenia patients, resistant to anti-psychotic drug treatments and associated with social functioning. In the first study, we examined the effects of affective salience of the target on spatial working memory. Increasing the salience of the target facilitates working memory in schizophrenia patients and the affective valence of the target contributes to the improvement. In Study 2, we examined the role of social (human) vs. non-social (computer) reinforcement on working memory and found that only the human, social reinforcement facilitates working memory in schizophrenia patients. In Study 3, the role of positive mood arousal on working memory was examined. We manipulated the mood arousal by showing film clips. Salivary cortisol levels, heart rate, and blood pressure were measured. Facilitation of working memory in schizophrenia occured after they viewed a film clip which invites participation by the patient but not after viewing a comic clip which does not invite participation. These results suggest that affective and social modulation of working memory function is significant in schizophrenia and point to the importance of integrating “affect” and “cognition” in studies of frontal lobe function.

223. REELIN AND GAD67 DOWNREGULATION AND PSYCHOSIS VULNERABILITY E. Costa, C. Pesold, J. Auta, H. Caruncho, J.M. Davis, G. Davidkova, Y. Dwivedi, D.R. Grayson, M. Rodriguez, D.P. Uzunov, A. Guidotti The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612 Reelin (RELN) is an extracellular matrix (ECM) protein synthesized and released by GABAergic interneurons (horizontal, bitufted, Martinotti cells) in cortex. The interaction of RELN with a putative receptor domain of the ECM triggers an intracellular transduction cascade phosphorylating disabled1 (DAB1) which functions as an adaptor protein facilitating transfer to the nucleus of specific tyrosine kinases which may initiate gene transcription. Because of the presence of RELN in GABAergic interneurons, and because of reduced GAD67 expression in prefrontal cortex (PFC) of schizophrenia patients, we studied RELN and GAD67 expression in PFCs, temporal cortices, hippocampi, caudate nuclei, and cerebella of schizophrenia and bipolar disorder patients with psychosis, depressed patients without psychosis, and of their matched (sex, age) nonpsychiatric control subjects1. In all brain areas analyzed, the content of RELN and GAD67 protein and mRNA is decreased (approximately 50%) in psychotic patients affected by either schizophrenia or bipolar disorder, but not in patients with unipolar depression without psychosis when compared with nonpsychiatric subjects. No differences among groups were found for GAD65, DAB1, or neuron-specific enolase (NSE) expression. In the PFC of schizophrenia and bipolar disorder patients with psychosis, the number of RELN-positive cells was decreased by 25–30% in the absence of neuronal loss. The decrease of RELN and GAD67 expression was not related to the time of death or sample freezing interval, and also failed to correlate with antipsychotic drug treatment. These findings suggest that RELN and GAD67 downregulation are associated with psychosis vulnerability. 1

Friday Abstracts

BIOL PSYCHIATRY 2000;47:1S–173S

Brain samples were obtained from the National Neurological Research Specimen Bank, Veterans Administration Medical Center (Los Angeles, CA); the Harvard Brain Tissue Resources Center, McLean Hospital (Belmont, MA), and the Stanley Foundation Neuropathology Consortium (Bethesda, MD).

224. PUTATIVE THALAMIC TERMINALS ARE DECREASED IN THE PREFRONTAL CORTEX IN SCHIZOPHRENIA D.A. Cruz (1), D.S. Melchitzky (1), D.A. Lewis (1,2) Departments of Psychiatry (1) and Neuroscience (2), University of Pittsburgh, Pittsburgh, PA 15213 Recent studies have reported decreased neuron number in the mediodorsal thalamic nucleus (MDTN), the principal source of thalamic projections to the prefrontal cortex (PFC), in subjects with schizophrenia. In thalamic relay nuclei, the calcium binding protein parvalbumin (PV) is present in the neurons that provide the major thalamic projection to the cortical layers deep 3-4. In ultrastructural studies of area 9 in monkey PFC, we found PV immunoreactivity in axon terminals forming Gray’s Type I (excitatory) synapses exclusively in layers deep 3 and 4 (Melchitzky, et al., J Comp Neurol, 1998). In order to test the hypothesis that schizophrenia is associated with altered thalamic inputs to PFC, we examined PV-immunoreactive varicosities in PFC area 9 of 20 pairs of schizophrenic and control subjects matched for age, sex, and postmortem interval. Systematic random sampling techniques were used to quantify the density of PV-immunoreactive varicosities in 1 ␮m thick sections. The density of PV-positive varicosities did not differ between schizophrenic and control subjects in layers 2-superficial 3, whereas a significant (p ⫽ .006) decrease (24%) was found in layers deep 3-4 of the schizophrenic subjects. PV-positive axon terminals from cortical local circuit neurons are present in both superficial and middle cortical layers. Since the reduction in PV-labeled varicosities was present only in the middle zone, these findings suggest that the PV-positive terminals from thalamic relay nuclei are decreased in schizophrenia. These data are convergent with the results of other postmortem studies demonstrating altered thalamic-prefrontal cortical connectivity in schizophrenia. Supported by MH00519 and MH45156.

225. VOLUMETRIC MAGNETIC RESONANCE IMAGING IN TWINS CONCORDANT AND DISCORDANT FOR SCHIZOPHRENIA T. Sharma, N. Davies, T. Ribchester, X.A. Chitnis, R.M. Murray Section of Cognitive Psychopharmacology, Department of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF Studies of identical twins are an ideal way to examine genetic and non genetic aetiological factors in schizophrenia. We used structural MRI to examine brain structure in 13 twins pairs concordant for schizophrenia and 12 discordant pairs. They were compared to 16 pairs of age and gender matched normal twins. Both the ill and well twins in the discordant pairs had significantly smaller whole brain volumes, cortical grey matter and amydala than normal control twins. However the ill twins also had smaller temporal lobes (and grey matter), hippocampi as well as increased lateral and third ventricles when compared to normal control twins. Within the discordant pairs, the ill twin had significantly smaller prefrontal cortical and hippocampal volumes than their well twin. Compared to 26 concordant twins, the 12 discordant schizophrenic twins exhibited smaller whole brain volumes, left and right hippocampi and larger third and lateral ventricles. There were no statistical differences in cortical grey matter, temporal lobes or

Friday Abstracts

amygdala volumes between the groups though the discordants schizophrenic twins were numerically smaller in size in all the brain regions measured. This study replicates our previous work of structural brain abnormalities in unaffected family members who are at high risk of developing schizophrenia. The evidence of greater structural brain abnormalities in discordant schizophrenic twins (who are likely to have lower genetic loading than concordant twins) may point towards environmental factors that may operate in aetiology of structural brain abnormalities in schizophrenia.

BIOL PSYCHIATRY 2000;47:1S–173S

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227. MENSTRUAL-RELATED CHANGES IN CORTICAL EXCITABILITY IN WOMEN WITH PMS AND CONTROLS M.J. Smith, B.D. Greenberg, L.F. Adams, M. Nguyen, P.J. Schmidt, D.R. Rubinow, E.M. Wassermann (2) National Institute of Mental Health; (2) National Institute of Neurological Diseases and Stroke, Bethesda, MD 20892

226. TRANSIENT OCCUPANCY AT THE D2 RECEPTOR—A NEW HYPOTHESIS FOR ATYPICAL ANTIPSYCHOTICS S. Kapur (1,2), P. Seeman (2) (1) Schizophrenia Program of the Centre for Addiction and Mental Health and (2) University of Toronto at Toronto, Toronto, Ontario, Canada. M5T 1R8 In the last few years there have been a number of new antipsychotics which cause a lower incidence of extrapyramidal side-effects and/or prolactin elevation as compared to high doses of haloperidol. Since all these “atypical” antipsychotics have relevant affinities for the D2 receptor it has been thought that it is the ratio of 5-HT2/D2 or D4/D2 affinity of these drugs account for their favorable profile. We challenge these hypotheses and propose a new alternative. We base our hypothesis on several pieces of data. In particular, on PET studies that show: i) even haloperidol can give an “atypical” antipsychotic effect with the right D2 occupancy; ii) that the freedom from EPS relates not to high 5-HT2 occupancy, but, to low D2 occupancy; iii) that transiently high daily D2 occupancy is sufficient for antipsychotic effect. This is supported by data in animal models which shows that: iv) transient D2 blockade is also sufficient for antipsychotic effect in animals; v) that some previous differences between typical vs. atypical antipsychotics may reflect a dosing confound. Finally, we base our claim on in vitro data which shows that: vi) the single most powerful predictor of “atypicality” is not the affinity of drugs at other receptors (5-HT2 or D4) but their fast dissociation (koff) at the D2 receptor. Based on these data we will present a “transient occupancy hypothesis” that is a sufficient explanation for atypical antipsychotic effect. The significance of this hypothesis for understanding antipsychotics and designing newer ones will be discussed. Thanks to MRC, EJLB, NARSAD and Stanley Fdn.

Neurobiology I Friday, May 12, 2:30 PM–5:00 PM Location: Wrigley Chair: Mark A. Geyer

Ovarian steroids modulate cortical excitability, which increases with estradiol (E2), possibly through glutamate potentiation, and decreases with progesterone (P4) metabolites, through the GABA-A receptor. Paired-pulse transcranial magnetic stimulation (pTMS) non-invasively measures intra-cortical inhibition and intra-cortical facilitation, which may be modulated by the cortical glutamate/GABA balance. A previous study in 13 normal women showed increased inhibition and decreased facilitation, suggesting P4-enhanced GABA activity, in the mid-luteal phase (days 18 –27) of the menstrual cycle compared to the follicular phase (days 5–12). In a subsequent study, pTMS was performed in normal women at 3 times: early follicular (days 2–5), late follicular (days 9 –12), luteal (6 –11 days post LH surge) and the ratios of the amplitude of conditioned stimuli were compared to those of unconditioned stimuli. Repeated-measures ANOVA shows a significant cycle phase effect on these ratios (F[2, 30] ⫽ 2.6; p ⬍ .05), with less inhibition and more facilitation during the late follicular (high E2, low P4) phase compared to either the early follicular (low E2, low P4) or the luteal (high E2, high P4) phases. Preliminary data in women with premenstrual syndrome suggest altered cortical excitability pattern and amplitude in the mid-follicular and luteal phases compared to controls. Thus menstrual cycle hormones may modulate GABA/glutamate balance. However, the effect on cortical excitability differs between normal women and women with PMS.

228. A GENOME SCAN USING A PHARMACOGENETIC APPROACH INDICATES A SUSCEPTIBILITY LOCUS FOR BD ON 15q14 G. Turecki (1), P. Grof (2), E. Grof (2), V. D’Souza (1), P. Cavazzoni (2), A. Duffy (2), C. Brewer (1), T. Hudson (1), G.A. Rouleau (1), M. Alda (2) (1) Douglas Hospital Research Institute, Department of Psychiatry, McGill University, Montreal, QC, H3H 1A4, Canada, (2) Affective Disorders Clinic, Royal Ottawa Hospital, University of Ottawa, ON, KIZ7K4, Canada A large number of studies have been carried out over the last years trying to identify the loci implicated in the etiology of bipolar disorder (BD), however, they have been flooded by inconsistent results of difficult interpretation. One of the possible reasons for this scenario is the substantial presence of genetic heterogeneity, and among the suggested approaches to circumvent this problem, a pharmacogenetic strategy has been increasingly proposed. Several studies have indicated that patients with bipolar disorder who respond well to lithium prophylaxis constitute a biologically distinct subgroup. In this study we have conducted a complete genome scan using 378 markers spaced at an average distance of 10 cM in 31 families ascertained through excellent lithium responders. Response to lithium was evaluated prospectively with an average follow-up of 14.4 ⫾ 6.8 years. Significant evidence for linkage was