Topographic change in EEG photic driving following clozapine

SATURDAY,, MAY 20

tween MEO and FLO was even milder than that between the FEO and MLO. In conclusion, gender difference in SCH has differential meaning in community-living and long-stay SCH cases. Gender social role and age of onset were two major factors for understanding the gender difference in SCH. Early-onset cases were found to have higher familial tendency of psychosis in both male and female SCH cases.

272. CHANGES IN EEG RESONANCE FOLLOWING SDZ MAR 327 TREATMENT Y. Jin, J. Pham, S.E. Moayeri, J. Telford, & S.G. Potkin D e p a r t m e n t o f Psychiatry and H u m a n Behavior, U C I Medical Center

BIOL PSYCHIATRY 1995;37:593-683

669

with the previous findings, the EEG responses were inversely correlated to patients' BPRS score (r < -0.57, p < 0.05). Partial correlation analysis removing the linear effect of the plasma level revealed a negative correlation between the EEG photic driving at 6.125 Hz and the positive BPRS score (r <-0.58, p > 0.05). No correlation was observed between the EEG and the negative BPRS score (NS). Conclusions: (1) The previously reported relationship between the EEG alpha activity and negative symptoms may be due to the fact that both measures share a common variance with the neuroleptic treatment. (2) Photic driving at low frequency band may serve as a predictor for the clinical response of positive symptoms to the clozapine treatment.

274. SELECTIVE ATI'ENTION IN SCHIZOPHRENICS MEASURED BY A MODIFIED LABERGE TASK SoE. Moayeri, S.G. Potkin, & Y. Jin

The objective of this study was to ascertain the relationship between treatment with SDZ MAR 327, a novel atypical neuroleptic, and EEG changes in photic driving. Nine patients with DSM-III-R diagnosed schizophrenia were included in this self-controlled study. Patients were drug-free for 2 weeks before entering clinical trials with MAR 327. EEG data was collected at the ends of washout and 3-month treatment. The EEG was performed under two experimental conditions: resting and 1 Hz light flickering stimulation. The resting EEG was assessed according to the total power of the whole spectrum (<35 Hz) and four consecutive bands (delta: 0-4 Hz; theta: 5-7 Hz; alpha: 8-13 Hz and beta: 14-25 Hz). The photic driving was measured at the harmonic frequencies of the stimuli. I.x)wer stimulation frequency in time domain produces higher harmonic resolution in frequency domain. Therefore, with this 1 Hz photic stimulation, the brain resonant response was able to be extracted and depicted by the corresponding curve fitting. No differences were observed in the resting EEGs between the drug-free and treatment conditions (p > 0.10). EEG photic driving was significantly increased following MAR 327, particularly in the alpha and beta bands (p < 0.03). Averaged data showed that the treatment not only sharpened the resonance (Q factor increased form 3.4 during washout to 9.6 with treatment) but also increased the peak frequency (from 9.8 Hz in washout to 11.4 Hz with treatment). The pharmacological and clinical significance will be discussed.

273. RELATIONSHIP AMONG CLOZAPINE LEVEL, EEG PHOTIC DRIVING, AND CLINICAL SYMPTOMS

Y. Jin, L. Tjahjono, C. Cezar, S. Moayeri, B. Gerber, & S. Potkin D e p a r t m e n t o f Psychiatry and H u m a n Behavior, U C I Medical Center Clozapine treatment normalizes the schizophrenic deficit in EEG resonant response to flickering light stimulation. The current study was designed to test the relationship among the clozapine plasma concentration, EEG photic driving, and clinical symptoms. Sixteen schizophrenics were included in a double-blind clinical trial. Patients were randomly assigned to one of the two clozapine treatments with 400 mg/day or 800 mg/day. Blood samples, EEG data, and clinical ratings were collected at the end of an 8-week treatment period, when the steady state of clozapine plasma level was theoretically reached. Patients' clozapine plasma concentration was significantly correlated with the power density of EEG photic driving in the theta and low alpha frequency range (r > 0.55, p < 0.05) but not in the delta, high alpha, and beta ranges (NS). These changes in the photic driving were primarily located at frontal and central areas. Consistent

D e p a r t m e n t o f P s y c h i a t r y and H u m a n Behavior, U C I Medical Center The objective of this study is to employ a novel psychophysiological task in order to measure selective visual attention between schizophrenics and normals. The LaBerge task quantitatively measures narrow and wide visual attention. We pilot tested this task in normals and schizophrenic subjects. Five of the 12 normal subjects and only one of the six patients could complete the task with fewer than 20% errors and misses, which questioned the validity of the test. We, therefore, modified the task. All 12 normals and 15 of the 21 schizophrenics completed the new task with an error and miss rate of less than 20%; they did not differ from one another (Fisher exact test, p = 0.52). Comparing reaction times, normals performed faster on the modified task than the original LaBerge task (435 msec vs. 700 msec, p < 0.01); however, within normal subjects the LaBerge task did not demonstrate a significant difference between the narrow versus wide condition (693 msec vs. 706 msec, p = 0.63); whereas, the modified task did (418 msec vs. 452 msec, p = 0.03). On the modified task, schizophrenics had an overall longer reaction time than normals (583 msec vs. 435 msec, = 0.001), and unlike normals they did not have an appreciable difference between the narrow and wide conditions (581 msec and 585 msec, p = 0.82). The number of misses on the wide condition, but not the narrow condition, are correlated to patient's symptoms (r = 0.49, p < 0.05).

275. TOPOGRAPHIC CHANGE IN EEG PHOTIC DRIVING FOLLOWING CLOZAPINE

Y. Jin, S.G. Potkin, J.C. Wu, J. Telford, & C. Sandman D e p a r t m e n t o f P s y c h i a t r y and H u m a n Behavior, U C I Medical Center Schizophrenic patients have lower EEG photic driving than normal subjects. Clozapine treatment normalizes the deficit, especially in the clinical responders. The aim of this study was to replicate the previous findings in a better controlled situation and to further illustrate the topographic distribution of the change in photic driving following the treatment. Thirty-one patients with DSM-III-R diagnosed schizophrenia (mean age: 31.5 + 8.8; sex: 19 males, 11 females) were tested in an EEG photic driving paradigm following treatment with clozapine, Haldol® (haloperidol), and placebo. Compared to placebo, clozapine and Haldol decreased the spontaneous and stimulus evoked EEG activities in the beta band. Both neuroleptics had the similar topographic pattern of decreasing the high-frequency

670

SATURDAY,, MAY 20

BIOL PSYCHIATRY 1995;37:593 683

photic driving, spreading diffusely over the whole scalp. Clozapine and Haldol did not affect delta frequency. Clozapine but not Haldol increased the spontaneous theta activity and the photic driving in theta and low alpha frequency range. The increase in the low frequency activities following clozapine were primarily located in the frontal and the mid-centroparietal areas. There were no significant changes in the lateral and posterior regions of the brain. The generalized decrease in high-frequency EEG photic driving suggests that both Haldol and clozapine decrease the arousal level. The lack of a treatments effect on delta activity suggests that our observed EEG changes with Haldol and clozapine are not the sedative effects. Clozapine's unique effect on the EEG theta activity and its topographic distribution may be related to its high affinity for the 5-HT 2 receptor in the cortex.

276. EYE-MOVEMENT DYSFUNCTIONS IN SCHIZOPHRENIA: STATE OR TRAIT? M. Obuchowski & B. Comblatt Mt. Sinai School o f Medicine, N e w York, NY 10029 Neurobehavioral abnormalities are frequently associated with schizophrenia; however, it is unclear whether these deficits are traits (i.e., stable and enduring) or state related (i.e., fluctuate with illness). Early, stable deficits would support the current view of schizophrenia as a neurodevelopmental disorder, whereas progressive deficits suggest a neurodegenerative illness. Eye movement dysfunctions (EMDs), long considered to be a trait associated with schizophrenia, can help test these competing hypotheses, since some reports suggest that EMDs deteriorate with chronic illness. In this study, we will use infrared oculography to determine whether EMDs found at the onset of schizophrenia deteriorate as the illness progresses. Two groups of patients representing different stages of illness (recent onset and chronic multiepisode patients) will be compared on several quantitative EMD measures previously found to be characteristic of patients with schizophrenia (pursuit integrity, frequency, and types of saccades). Lesser eye-tracking impairment in the early-stage schizophrenia patients compared to multiepisode chronic patients suggest that EMDs deteriorate with illness. In contrast, a similar pattern of EMDs among patients with variable illness durations suggests that EMDs are a trait deficit and supports the neurodevelopmental view of schizophrenia.

277. SUPPORT FOR A NEURODEVELOPMENTAL VIEW OF SCHIZOPHRENIA B. Cornblatt l, M. Obuchowski I, K. Osgood j, L. Erlenmeyer-Kimling 2, & D. Schnur I tMt. Sinai School o f Medicine, New York, NY 10029; 2Columbia University College o f Physicians and Surgeons, New York, NY 10032 Although direct data is limited, schizophrenia has been increasingly considered a neurodevelopmental rather than a neurodegenerative disorder. In this report, we present attentional data that supports the developmental view. A total of 70 subjects, divided into three groups representing different stages of schizophrenia, were tested on the Continuous Performance Test, Identical Pairs version. The first group consisted of 28 offspring of schizophrenic parents, tested several years ago as part of the New York High Risk project, some of whom have since developed adult schizophrenia. Groups 2 and 3 consisted of patients with schizophrenia hospitalized at Elmhurst Hospital Center. Patients in group 2 (n = 26) were in their first year of illness; those in group 3 (n - 16) had been ill for a minimum of 10

years. It was hypothesized that an increase in attentional deficits from preillness to first year to multiepisode would support a deteriorative disease process, whereas stable impairment would suggest a developmental course. High-risk offspring who have remained symptom-free as adults performed similarly to normal controls when tested as adolescents. By contrast, preschizophrenic high-risk adolescents were highly impaired in their attention relative to controls and did not differ from already affected patients. Moreover, no differences were found between already affected patients as a function of chronicity. Thus, attention appears to be a stable trait that is impaired at the earliest stages of illness (even prior to clinical expression) and that does not change with clinical deterioration--thus supporting a developmental view of the illness process.

278. SELECTIVE AGE-RELATED REDUCTIONS IN FRONTAL LOBE FUNCTION M.J. Hoptman I & R.J. Davidson 2 INathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962; 2Department of Psychology, University o f Wisconsin-Madison, Madison, WI 53706 Neuropsychological tests were administered to 32 younger (aged 18-36 years) and 27 older (aged 60-88 years) subjects. Subjects were righthanded, and were screened for history and presence of major psychiatric disorders. Older subjects had Mini Mental Status Examination scores of at least 26, and groups were matched on socioeconomic status, dispositional affect (as measured by the PANAS-Gen), and depression scores (as measured by the Beck Depression Inventory). Older subjects were given a medical examination by a geriatrician. Subjects were given the neuropsychological tests in a single 2.5-hour session. Thurstone Verbal Fluency and the Tower of London tasks were used to sample frontal lobe function (based on lesion study data; these have been found to be selectively sensitive to frontal damage). Word Finding and Dot Location tasks were used to sample parietal lobe function. Finally, Hebb's Recurring Digits and Corsi's Recurring Blocks tests were used to sample temporal lobe function. Hierarchical regression analyses showed that frontal lobe tests predicted more of the variance in age than did temporal and parietal lobe tests. These results are consistent with previous literature on neuropsychological changes in aging. Additional analyses suggested that some of the effects of frontal lobe tasks may be related to motor functioning and others may be related to nonmotor functioning, suggesting that decomposition of the tasks' motor and nonmotor aspects may be fruitful.

279. NONSENSE CHANGE IN THE D5 DOPAMINE RECEPTOR GENE SEARCH FOR BEHAVIORAL PHENOTYPES D.H. Zald l, B.E. Snitz ~, J.L. Sobell 2, ToJ. Lind 3, L.L. Heston 4, S.S. Sommer 3, & W.M. Grove I IDepartment o f Psychology, University o f Minnesota, Minneapolis, MN; 2Department o f Psychiatry and Psychology and Department of Health Sciences Research, Mayo Clinic/ Foundation, Rochester, MN; 3Dept. o f Biochemistry and Molecular Biology, M a y o Clinic/Foundation, Rochester, MN: 4Department o f Psychiatry, University o f Washington, Seattle, WA A bauer3,' of neuropsychological, psychophysiological, and personality tests was administered to a family known to be segregating for a nonsense change in the D5 dopamine receptor gene. The variant allele (C335X) is predicted to prematurely truncate the receptor protein and result in a 50%