Stress and schizophrenia: New neurochemical findings and models

69

immunoaffinity purified rabbit antiserum against human N-CAM. There were no significant medication withdrawal or exacerbation effects, indicating that these factors probably do not account for the elevation of CSF N-CAM in schizophrenic patients. Drug-free schizophrenic patients had significantly higher drug free CSF NCAM levels than the control subjects (z= -6.40, p<0.0005) as well as significantly higher variance in N-CAM levels(F= 12.60,d/= 19,44,p< 0.0005). In addition, the range of CSF N-CAM values for the control subjects (4O.7-105.2ng/ml) did not overlap with the range for the schizophrenic group (113.7-358.3 ng/ml), Increased N-CAM levels are consistent with both an early static lesion as well as a progressive lesion of the brain in schizophrenia; further studies using brain structural measures may address this issue.

IQZ THE ROLE OF IMMUNE MEASURES IN PSYCHOSIS AND STRESS SENSITIVITY IN SCHIZOPHRENIA Daniel P. van Kammen, Cathy G. McAllister, Mary E. Kelley, Alexander A. Mathe, Walter A. Brown, Jeffrey K. Yao, John A. Gurklis Veterans Affairs Medical Center, 7180 Highland Drive, Pittsburgh. PA 15206

Recent studies have raised the issue as to whether the reported immune disturbances in schizophrenia may be the result of a stress induced dysregulation of CNS cytokine production, rather than a permanent ~unological disorder, i.e., autoimmunity. Our group has previously shown that the cytoldne interleukin-2 (11.-2), but not interleukin 1 (11.-1), in the CSF was elevated in haloperidol treated patients who relapsed within 6 weeks foll~~g ~rug withdrawal. :nus indicated a possible stress sensiuvtty 1Il the relapsed patients which could be identified using CSF immune measures. In an attempt to uncover evidence of a direct effect of the immune system on brain function, we examinedthe relationship between immune measures and psychosis in 36 schizophrenic patients. After determining which immune measures were significant predictors of psychosis, we attempted to control for elements associated with the two proposed mediums of the immune system and brain: the HPA axis (CSF, CRF, CSF prolactin or CSF AcrH and CSF cortisol), and the sympathetic nervous system (CSF NE). IL-IO was the only immune measure found to correlate with psychosis [r=0.51, d/=34, p=O.OOI). When 11...-10, NE, and the HPA variableswereentered into a regression predicting psychosis levels on medication, both 11.-10 and cortisol were significantpredictors of psychosislevels,indicating a possible direct effect of IL-IO on behavior. However, drug free data on the same patients and measures revealed that

cortisol, but not 11.-10, was significantly associated with psychosis. ,~

CELLULAR EFFECTS OF SERUM OSMOLARITY CHANGES IN POLYDIPSIA· HYPONATREMIA Cherian Verghese, M.D.; Irena Levitan. Ph.D.; Sarah Garber, Ph.D.; Chand Nair, M.D.; George Abraham, M.D.; Richard Josiassen, Ph.D. Allegheny University/NSH Clinical Research Center. 1001 Sterigere Street, Norristown . PA 19401

Polydipsia-hyponatremia (PH), a disorder of water balance, affects 25% of chronic schizophrenics. Osmolar disturbances are very rare in the general population. PH is characterized by excessivewater intake and an inability to fully excrete ingested water, resulting in serum hyposmolarity. PH shows significant diurnal variation in serum osmolarity, in contrast to the constant osmolarity in normals. Cells, especially brain cells, are very sensitive to changes in osmolarity. Polydipsics are known to have more cognitive deficits and decreased brain tissue compared to schizophrenics without PH. Using peripheral blood lymphocytes as a model to study osmotic regulation in response to hyposmolarity, we compared lymphocytes from schizophrenics with PH to those of normal controls. Cells were subjected to a 50% hyposmolar shock and the increase in cell volume was studied over time using light microscopy. Baseline volumes were comparable in the two groups. After 30 minutes, normal cells returned close to baseline volume, but PH cells were unable to respond with a regulatory volume decrease, and had significantly greater volumes. Our findings suggest that cellular volume regulation may be altered in patients with PH. This could contribute to the increased cognitive deficits and decreased brain tissue seen in schizophrenics with PH. Support: NARSAD Young Investigator Award, AHA 94002340 and NSF BIR9413528.

I(!

STRESS AND SCHIZOPHRENIA: NEW NEUROCHEMICAL FINDINGS AND MODELS Elaine F. Walker, Donald Diforio, Colleen Logan Department 0/ Psychology, Emory University. Atlanta Georgia 30322

Diathesis-stress models of schizophrenia have dominated theorizing for several decades. In this presentation, parallels between findings from the psychosocial and neuroendocrine research will be reviewed. Like the research on psychosocial stressors, the literature on hypothalamic-pituitary-adrenal (HPA) system function suggests that schizophrenia is charac-

70

187 terized by heightened sensitivity to stress. Recent findings from our research will be presented, indicating that cortisol release is also heightened in subjects with schizotypal disorder, and that biological stress sensitivity may be a triggering factor for psychotic symptoms. A neural mechanism for these phenomena is suggested by preclinical findings that there are augmenting effects of the HPA axis on dopamine (DA) synthesis and receptors. Conversely, DA activation stimulates the HPA axis. Drawing on evidence that the diathesis for schizophrenia involves an abnormality in DA neurotransmission, it is proposed that the HPA axis acts as a potentiating system which moderates the expression of the diathesis via its effects on DA-mediated circuitry. Concomitantly, the DA abnormality and hippocampal damage can render the individual hypersensitive to stress. This neural diathesis-stress model is consistent with findings on prenatal factors and hippocampal abnormalities in schizophrenia, and it provides a frame-work for explaining some key developmental and clinical features of the illness.

I~

SKIN FLUSHING IN RESPONSE TO GRADED DOSES OF TOPICAL NIACIN: A NEW TEST WHICH DISTINGUISHES SCHIZOPHRENICS FROM CONTROLS P. Ward, J. Sutherland, E. Glen, A.I.M. Glen and ·D.F. Horrobin. Highland Psychiatric Research Group, Inverness, Scotland, Scotland IV3 6JU and "Scatla Research Institute, Stirling, Scotland FK9 4TZ

Oral niacin in a dose of 200mg produces skin flushing in normal individuals due to release of arachidonic acid (AA) from mast cell phospholipids by the enzyme phospholipase A 2 and the conversion of AA to vasodilator prostaglandin 02. About 20-40"10 of schizophrenics, predominantly those with the negative syndrome, do not flush. The oral test is all or nothing and does not permit quantitative assessment. We have therefore devised a top ical test in which a strip impregnated with 0.1, 0.01, 0.001 and 0.0001 M niacin is applied to the forearm skin and the redness (or oedema in dark skin) is read after 5 minutes on a simple 0-3 scale. 38 schizophrenics with various sub-types of the syndrome were compared to 22 controls. At all concentrations the response in the schizophrenic group was dramatically less than in the control group (p
OBSTETRICAL COMPLICATIONS AND STRESS-RESPONSITIVITY IN ADOLESCENTS AT-RISK FOR SCHIZOPHRENIA Dana Davis Weinstein, Rachel Lowey, Donald Diforio, and Elaine F . Walker Department ofPsychology. Emory University. Atlanta. Georgia 30322

It has been reported that obstetrical complications during the prenatal period increase the risk for schizophrenia (Green, Bracha, Satz, & Christenson, 1994) and are associated with increased ventricular and reduced hippocampal size in adult schizophrenia patients (Cannon et al., 1993; Delisi, Dauphinais, & Gershon, 1988). Further, hippocampal damage has been related to increased secretion of the stress hormone cortisol (Sapolsky, Krey, & McEwen, 1986). This suggests that enhanced cortisol secretion in schizophrenia patients (Sharma et al., 1988) may be secondary to hippocampal damage produced by obstetrical complications. Enhanced cortisol secretion may impact symptom expression in schizophrenia because cortisol secretion is believed to enhance dopamine transmission (Walker, 1994). We have collected data 00 obstetrical complications, cortisol secretion, and symptomatology in adolescents between the ages of 12 and 18 meeting DSM-I1I-R criteria for schizotypal personality disorder, other personality disorders, and no disorders.

t1( NEUROLEPTIC EFFECTS ON ANTIOXIDANT DEFENSE SYSTEM ENZYMES IN SCHIZOPHRENIA Jeffrey K . Yao, Daniel P. van Kammen, Ravinder D. Reddy Department of Veterans Affairs Medical Center (High/and Dr.}, Pittsburgh. PA 15206

Previous studies have suggested a potential for oxidative stress and subsequent membrane pathology in schizophrenia. Deregulation of free radical metabolism as reflected by abnormal erythrocyte activities of three critical enzymes of the antioxidant defense system (AODS), i.e.• superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT). has been reported in schizophrenic patients. It is not clear, however, whether such a defect results from a long-term treatment of neuroleptics. The purpose of the present study was to assess the neuroleptic effects on the AODS enzymes in schizophrenic patients, using a within-subject , repeated measures , on-off-on haloperidol treatment design. SOD, GSH-Px,