Limbic cortical serotonin 1A receptor mRNA in schizophrenia

682

SATURDAY,, MAY 20

BIOL PSYCHIATRY 1995;37:593-683

cesses of plasma 3-methoxy-4-hydroxy-phenylglycol (pMHPG). The dopamine psychosis patients were diagnostically (DSM-III) heterogeneous: 40% schizophrenia, 13% schizophreniform disorder, and 47% affective psychoses. SADS symptom clusters did not differentiate the dopamine psychotics from other psychoses. A superior antipsychotic response by the dopamine psychotics was evident by day 4 following initiation of antipsychotic drug. ANCOVA with baseline +BPRS scores as the covariate revealed superior antipsychotic response discernible by the 4th day of drug treatment (F = 10.1, p < 0.007). Plasma haloperidol levels did not differ between the two groups (4.1 + 3.0 vs. 4.7 + 2.4 at day 7; 7.1 _+6.7 vs. 7.3 + 2.9 at day 14). From day 10-28 of drug treatment, the slopes of response were essentially parallel in the high- and low-pHVA groups. The difference in response rates during the first 7 days of treatment set the course for the remainder of the treatment period. The pedigrees of dopamine psychosis probands exhibited additional members with psychotic disorders. It may be necessary to segregate pedigrees by markers of the underlying disease (such as pHVA) for the next generation of genetic linkage studies in the psychoses.

318. HETEROGENEITY OF THE PSYCHOSES: II. NEURO-DEGENERATIVE PSYCHOSIS D.L. Garver 1,2, F. Sautter 3, J. Knoll l , J. Hirschowitz 4, J. Steinberg 1,2, N.G. Kumar 1,2, & J. Griffith 1,2 ~Southwestern Medical Center o f the University o f Texas; 2Dallas VA Medical Center, Dallas, T X 75216; 3 Tulane College o f Medicine, N e w Orleans LA; 4Bronx VA Medical Center, Bronx, NY 10468 The "Group of the Schizophrenias" has not been resolved into its component diseases. There is growing evidence that several psychotic disorders or diseases can be differentiated from one another. One disease appears to be associated with a premature disappearance of brain substance. Significant increase in ventricular-brain ratios (VBRs) over periods of 2-8 years is indicative of an active, ongoing disappearance of brain substance. Our meta-analysis of the CAT-VBR brain literature in patients meeting syndromal criteria for "schizophrenia" documents a bimodal pattern of changes in VBR (p < 0.001 ). A significant subgroup (35%) of schizophrenics evidence premature loss of brain substance together with progressive ventriculomegaly outside the 95% confidence level of the method. Maximal increases in VBR were found in two schizophrenics in their early 20s; a significant though smaller increase in VBR was found in patients from the mid-20s to the 50s. In contrast, 22 schizophrenics (65%) failed to demonstrate significant change in the VBR during periods of 2-8 years. Ventricular size increases with age, hut such increases are not apparent with brain imaging techniques until the 6th and 7th decades of life. A 30-year "'shiftto-the-left" of third ventricular size-age relationship was found in a subgroup (13 of 34[42%]) of psychotic patients. The 13 "shifted" patients belonged to a subgroup of psychotic patients which was characterized not by differences in symptoms, but by a characteristically delayed response (2-5 weeks for reduction of psychosis scores by 55%) following initiation of haloperidol. When hospitalized for a subsequent epistxle of psychosis, such patients required longer periods of treatment than at index admission to meet response criteria. The remaining 22 psychotic patients who showed no comparable ventricular-age relationship (across an age range of 17-50 years), had different response patterns following initiation of treatment. The pedigrees of such neurodegenerative psychosis probands exhibited additional members with psychotic disorders. It may be necessary to segregate pedigrees by markers of the underlying disease (such as progressive, premature increase VBR or, perhaps, changes in phospholipids or in N-acetylaspartate on MR spectroscopy) for the next generation of genetic linkage studies in the psychoses.

319. THE EFFECT OF STATE ON AUDITORY P50 GATING IN SCHIZOPHRENICS AND NORMALS J.M. Griffith 1,2, J.E. O'Neill l, R. Armitage 2, & D.L G a r v e r 1,2 tThe Department o f Veterans Affairs Medical Center, Dallas, T X 75216; 2The University o f Texas Southwestern Medical Center, Dallas, TX 75235 Schizophrenics' sensory processing deficits can be measured with tests such as the Auditory P50 Gating Paradigm. In this test, subjects are presented paired auditory clicks, and the middle-latency evoked response of the EEG (P50 wave) is assessed. In normals, the P50 wave response evoked by the second click is diminished relative to the response evoked by the first click. This is a demonstration of normal CNS inhibitory gating mechanisms. Schizophrenics, in contrast, demonstrate reduced suppression of their P50 response to the second of paired clicks, demonstrating a failure of CNS inhibitory gating mechanisms. Recently, we reported that NREM sleep transiently normalizes schizophrenics' Auditory P50 Gating deficit. We hypothesized that NREM sleep promotes reactivation of the CNS inhibitory gating mechanisms which are chronically fatigued in schizophrenics. In this study, we probed further the effects of NREM sleep by assessing Auditory P50 Gating in schizophrenics (n - 6) and normals (n - 6) across three states: waking, napping (during which stage I1 sleep was achieved), and immediately post-napping. Analysis of Auditory P50 Gating in these two groups revealed a significant repeated measures ANOVA interaction between subject group and state (F = 3.82, df = 2, 20, p < 0.05). These findings suggest that schizophrenics and normals differ in processing sensory information across states of waking, stage II napping, and wakefulness immediately after stage I1 sleep, At the time of presentation, we will report results obtained from a larger number of subjects and will discuss the implications of these findings as they relate to the neurobiology and reproducibility of the Auditory P50 Gating Paradigm.

320. LIMBIC CORTICAL SEROTONIN 1A RECEPTOR mRNA IN SCHIZOPHRENIA S.E. Bachus, T.M. Hyde, M.M. Herman, & J.E. Kleinman Clinical Brain Disorders Branch, N I M H at St. Elizabeths, Washington, DC 20032 Some of the more reproducible abnormalities in the neumpathology of schizophrenia involve serotonin 2 receptors and serotonin reuptake sites (1). Studies of cortical serotonin la (5-HTIa) receptor density in schizophrenia have been less consistent in their findings. We have investigated this question by utilizing in situ hybridization histochemistry with an 35S-labeled oligonucleotide probe for the human 5-HTIa receptor on slides of prefrontal, cingulate, and entorhinal cortex from schizophrenics (n = 7), normal controls (n = 7), neuroleptic-treated, nonschizophrenic controls (n = 6), and suicides (n = 7). Statistics were by two-way ANOVA. There was a statistically significant group effect (p -0.001 ), and an interaction between group and region (p = 0.001). When only the schizophrenics and normal controls were compared, however, there was not a statistically significant difference. Subsequent comparisons region by region indicated that mRNA for the 5-HT1 a receptor was elevated in the cingulate cortex of schizophrenics relative to normals (p - 0.04), but not relative to suicides or neuroleptic-treated controls. Levels did not differ statistically significantly in prefrontal or entorhinal cortex of schizophrenics relative to normal controls. These results do not add to our characterization of abnormalities in prefrontal and entorhinal cortex in schizophrenia, but rather

SATURDAY, MAY 20

lend further evidence to a growing body of evidence that finds normal 5-HTI a receptors in schizophrenics.

321. ABNORMAL SACCADIC EYE MOVEMENTS ASSOCIATED WITH POSITIVE FAMILY HISTORY SCHIZOPHRENICS B.D. Schwartz 2, B.A. O'Brien 2.3, W. J. Evans 1,2,3, B.E. McDermott 1, F.J. Sautter Jr. 1,2, & D.K. Winstead 1,2 ITulane University School of Medicine, Department o f Psychiatry and Neurology; 2Veterans Administration Medical Center; 3Tulane University, Department o f Psychology Smooth pursuit eye movement abnormalities are consistently observed in schizophrenic patients and their first-degree relatives, suggesting a genetic contribution for this disorder. Investigations of saccadic eye movements in schizophrenia have generally not revealed a consistent pattern of deficits, although antisaccade deficits have been observed in schizophrenics and their relatives. The present study was conducted to determine if saccade abnormalities are associated with a genetic subtype of schizophrenia. A family history research strategy was used to classify schizophrenics as either family history positive (FH ÷, i.e., at least one first- or second-degree schizophrenic relative) or family history negative (FH, i.e., no first- or second-degree relatives diagnosed as schizophrenic). Twenty-one FH ÷, 18 FH-, and 19 nonschizophrenic controls were assessed on a saccadic eye movement task. Saccade gain, latency, and peak velocity were compared for the three groups using a multivariate analysis of variance. The analysis revealed that the peak saccade velocity was significantly slower for the FH+ group as compared to the controls or FI-Igroup, while the controls and FIT- group did not differ. Both FH + and FH had significantly lower saccade gain for large saccades (16-30 degrees) than the control group. For small amplitude saccades (5-10 degrees), the FH + group had significantly lower pursuit then the FH- and control groups, which did not differ from each other. Saccade latency did not differ between the groups. These results suggest that saccade abnormalities are characteristic of a genetic form of schizophrenia. The neurophysiologic mechanism underlying these abnormalities likely comprises a rapidresponse, transient visual pathway involved in the targeting of saccadic eye movements.

322. THE EFFECTS OF SEROQUEL (ICI 204.636) ON PLASMA PROLACTIN IN PATIENTS WITH SCHIZOPHRENIA M.B. Hamner I, L.A. Arvanitis 2, B.G. Miller 2, C. Link 2, & W.W. Hong 2 ~Department of Psychiatry, Ralph H. Johnson VA Medical Center, Charleston, SC 29401; 2CNS Clinical Research. Zeneca Pharmaceuticals, Wilmington, DE 19897 Seroquel TM (ICI 204,636; Zeneca Limited, Wilmington, DE), a dibenzothiazepine with affinity for multiple brain receptors, is a potential atyp-

B1OL PSYCHIATRY 683 1995;37:593-683

ical antipsychotic. Seroquel is active in behavioral and electrophysiologic tests considered predictive of antipsychotic activity and satisfies the following pharmacologic criteria, which are putative predictors of atypicality: (1) a higher affinity for central 5-HT2 than D2 receptors; (2) limbic system selectivity, as evidenced by depolarization inactivation of A 10 but not A9 dopamine cells after chronic administration; (3) minimal dystonic liability in haloperidol-sensitized and drug-naive monkeys; and (4) transient elevations in prolactin (PRL) after acute administration in rats. Phase II clinical trial results support the prediction that Seroquel has a low propensity to produce extrapyramidal side effects. The PRL data from these trials are presented. We investigated the effects of Seroquel on PRL in three 6-week, multicenter, double-blind efficacy and safety trials. Study 6 ( 109 patients) compared Seroquel (75-750 mg/day) and placebo whereas Study 8 (286 patients) compared low (75-250 mg/day) and high (75-750 mg/day) doses of Seroquel and placebo. PRL was measured on Days 0, 21, and 42. Mean PRL decreased in all treatment groups in both studies. There were no significant differences between treatment groups in least squares means of the change from baseline to final observation (ANCOVA). Study 7 (201 patients) compared Seroquel with chlorpromazine (both 75-750 rag/day) and assessed PRL weekly. The decrease in PRL in the Seroquel group was significantly greater than the decrease in the chlorpromazine group at the final observation. These results suggest that Seroquel does not produce sustained elevations of PRL and support Seroquel's atypical profile.

323. PREFRONTAL SUBDIVISIONS, TEMPORAL LOBE, AND SCHIZOPHRENIA: AN MRI STUDY C.G. Wible, M.E. Shenton, R. Kikinis, F. Jolesz, &

R.W. McCarley Harvard Medical School Brockton VAMC, Brockton, M A 02401 Prefrontal abnormalities in schizophrenics have been inconsistently re[x)rted in both functional and structural or volumetric studies. Several magnetic resonance imaging (MRI) studies report reduced volume of the prefrontal cortex in schizophrenics, but almost an equal number of studies report no volumetric abnormalities. Inconsistencies in MRI reports could result from the assessment of prefrontal cortex (a functionally heterogeneous region) as a whole. Small, circumscribed abnormalities might be missed in measurements that include the entire prefrontal cortex. A method for subdividing the prefrontal cortex into anatomical areas was developed for use with MRi. Fourteen chronic schizophrenic and 15 control male right-handed subjects were matched on age, IQ, and parental socioeconomic status (SES). A 1.5 Tesla magnet was used to obtain 1.5 mm thick slices through the entire brain. Prefrontal gray matter was segmented using semiautomated image processing and then edited and subdivided using an image editor on a SUN workstation. A MANOVA using the factors group (schizophrenic versus control), area (orbital, inferior, middle, superior, cingulate, and frontal-pole), and side (right or left) showed no significant effects between groups. The subjects used in this study were previously shown to have left-lateralized volume reductions in several tetnpoml lobe areas. Volumes of the left anterior portion of several temporal lobe areas were highly correlated with volumes of left orbital, inferior, and middle prefrontal regions in schizophrenic subjects but not controls. These data suggest that prefrontal and temporal areas are affected in a parallel manner by some neurodevelopmental or pathological process in schizophrenic subjects.