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BIOL PSYCHIATRY 1995;37:593-683
268. AGGRESSION IN THE TREATMENT OF INPATIENTS WITH SCHIZOPHRENIA, USING THE OVERT AGGRESSION SCALE
ceptors and uptake carriers for other neurotransmitters are ineffective in displacing this binding. These studies show that substituted zacopride analogs are promising tools for both neuroimaging and autoradiographic studies of this intriguing serotonin receptor subtype.
T. Su, J. Tuskan, L. Tsao, & D. Pickar Experimental Therapeutics Branch, N I M H , Bethesda, MD 20892-1380 To investigate the relationship between aggression, clinical symptoms and biological parameters in schizophrenic patients, a retrospective chart review of 48 inpatients on a research ward was conducted. Overt Aggression Scale (OAS) ratings, BPRS ratings, plasma cholesterol, body weight, and CSF monoamine levels were collected during three treatment conditions~fluphenazine, placebo, and clozapine. Results include: 25 of 48 patients (52%) exhibited aggressive behavior; there were significant decreases in episodes of aggression between placebo (81 episodes), fluphenazine (19 episodes), and clozapine (3 episodes). OAS scores also declined with clozapine treatment (PBO = 11.2 _+ 13.7, FLU = 2.9 _+ 5.7, C L Z - 0.36 _+ 1.0, p < 0.01); BPRS thought disorder (TD) subscale scores correlated with a number of aggressive episodes and higher OAS scores during fluphenazine and placebo condition (p < 0.0l ); however, no correlation existed during clozapine treatment; patients with "high aggression" (episodes > 3, or OAS scores > 10) (n = 13), compared to patients with "low aggression" (n = 35), demonstrated younger age, lower body weight, and significant increases in CSF 5-hydroxyindoleacetic acid (5HIAA) from fluphenazine to placebo. These data identify several predictors of aggression in schizophrenia, indicating that clozapine may have a selective effect on aggression and suggesting that aggression in schizophrenia may be mediated by different mechanisms than in other psychiatric disorders.
269. 1-125-LIZAC, A NOVEL LIGAND BINDING WITH HIGH AFFINITY TO 5-HT-3 CNS RECEPTORS
270. RACE A N D SUBSTANCE ABUSE IN SCHIZOPHRENIA W.B. Lawson 1,2 & T. Gore 3 ~McClellan VA Medical Center, North Little Rock, A R 72114; 2University of A r k a n s a s for Medical Sciences, Little Rock, AR 72205; 3Howard University Medical Center, Washington, D C Racial differences in substance abuse patterns have been reported in the general population. More than half of schizophrenic patients may be substance abusers, yet racial differences in abuse patterns have not been examined. Such studies may be clinically significant, since black schizophrenics tend to have more symptoms and may be more likely to develop tardive dyskinesia. Drags such as cocaine are risk factors for worsening symptoms and abnormal involuntary movements. A survey of 50 black and 50 white schizophrenic veterans randomly selected from all nonrepeated admissions over the previous year showed that black patients were significantly more likely to be cocaine or cannabis abusers (p < 0.05). We further studied 69 black and 29 white DSM-IV positive schizophrenic veterans in a program for patients with concomitant schizophrenia and substance abuse disorders. Black schizophrenic veterans were significantly more likely to be abusers of cocaine and other stimulants but not of other drugs of abuse or alcohol (p < 0.001 ). No significant differences were seen between black and white schizophrenic substance abusers in age, education, or % employed. No racial differences were seen in duration of use for any drugs of abuse. No differences were seen in positive or negative symptoms, degree of depression, suicide attempts, or duration of psychiatric or substance abuse hospitalizations. Black patients were more likely to stay longer in this treatment program. Previously reported racial differences in schizophrenia may be a consequence of differences in usage of drugs of abuse.
W.A. Hewlett, T. de Paulis, D.E. Schmidt, B.L. Trivedi, N.S. Mason, & M.H. Ebert Vanderbilt University Medical Center Serotonergic agents have been employed in the treatment of multiple psychiatric disorders. Our understanding of the underlying rationale for their efficacy has been hindered by the complexity of the serotonergic system, with at least 14 receptor subtypes now defined. Among subtypes attracting significant attention with regard to treatment of clinical syndromes is the 5-HT-3 receptor. Antagonists at 5-HT-3 receptors may be useful in the treatment of anxiety, cognitive, and substance use disorders, as well as schizophrenia. As yet, however, few agents are available for autoradiographic studies of these receptors, and no agents have been used for in vivo imaging of these sites in the CNS. lodozacopride is a substituted benzamide that binds with high affinity to 5-HT-3 receptors (Kd-4 nM). We previously reported that another analog of zacopride, (S)-4-deamino-3methoxy-5-iodozacopride (I-125-MIZAC), binds with high affinity (Kd-l.5 nM) and specificity to 5-HT-3 sites in homogenates of rat brain. We now report that a new compound, (S)-5-chloro-2-( 1-It 251]iodopropen3-yl)oxy-3-methoxy-N-(3-quinuclidinyl) benzamide (I-125-LIZAC), binds with significantly higher affinity (Kd-0.3 nM) to these sites. Bemesetron-displaceable binding of 1-125-LIZAC is highest in hippocampus and posterior-lateral cortex and lowest in striatum and cerebel~ lure. In vivo uptake of 1-125-LIZAC shows a similar distribution. High concentrations (3 gM) of antagonists with high affinity for other 5-HT receptor subtypes (1A,B,D; -2A,C; -6; and -7) are ineffective in displacing 5-HT-3 specific 1-125-LIZAC binding. Similarly, antagonists at re.-
271. EPIDEMIOLOGY OF SCHIZOPHRENIA: GENDER A N D AGE OF ONSET H.G. Hwu, H. Rin, & L.L. Yeh D e p a r t m e n t o f P s y c h i a t r y , College o f Medicine, National Taiwan University, Taiwan This study was designed to test the hypothesis of 1) gender difference in psychopathology (PSYPAH) of schizophrenia (SCH), and 2) exaggerated difference in PSYPAH between the group of early-onset (20 y/o) male SCH and late-onset (30 y/o) female SCH cases. 2126 male and 1628 female SCH cases admitted over one-year period as the community-living patients, long-stay SCH patients of 3060 males and 1530 females were used as study sample. The community-living male SCH cases had earlier age onset, had a higher negative symptom score on admission, consisted of more persons who were single and without a job before admission, and needed a higher dosage of antipsychotics on discharge. The difference between early-onset male (MEO) and late-onset female (FEO) was not greater than that between the early-onset female (FEO) and late-onset male (MLO) groups. By analyzing the data of the long-stay SCH sample, the male group was found to have more persons who were single and more without a job before admission; however, the female group was fimnd to have higher familial tendency of psychosis and worse PSYPAH. No difference in age of onset was found. The difference in PSYPAH be-
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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
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