Electrodermal responsiveness, clinical variables, and brain imaging in male chronic schizophrenics

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Electro.dermal Responsiveness, Clinical Variables, and Brain Imaging in Male Chronic Schizophrenics Doh Kwan Kim, Young Min Shin, Chul Eung Kim, Hae Soo Cho, and Yong Silt Kim

We investigated the variables related to electrodermal nonresponsiveness in male chronic schizophrenics. In a comparison of 31 male chronic schizophrenics and 20 male normal controls, the schizophrenics showed a much higher incidence of nonresponders in phasic electrodermal responsiveness, and fewer spontaneous fluctuations (SFs ) in tonic electrodermal activity. Among the schizophrenics, nonresponders showed fewer SFs and lower tonic skin conductance level (SCL). They also had more neuropsychological abnormalities of cognitive function and more severe symptoms (both positive and negative). Furthermore, patients with structural abnormality of the brain revealed by computerized tomographic measurements (increased ventricular brain ratio and maximum diameter of third ventricle) were overrepresented among electrodermal nonresponding schizophrenics. These findings suggest that electrodermal nonresponsiveness in chronic schizophrenic illness might be considered as a functional index associated with greater neuropsychological abnormalities and more severe symptoms. Key Words: Electrodermal responsiveness, chronic schizophrenics, neuropsychological impairment, psychiatric symptom, brain imaging

Introduction One hallmark of schizophrenia is the vulnerability of cognitive processes to interference. Several authors identify a primary cognitive dysfunction of schizophrenics at the level of information processing (Frith 1981; Callaway and Naghdi 1982; Gjerde 1983). More considered approaches suggest that the disturbance is likely not to be found in an early automatic process but more likely in a later controlled information processing mechanism (limited-channel-capacity processes, LCCPs) in which the selection of the From the Department of Psychiatry, College of Medicine, Seoul I" ational University (DKK, YSK), the Department of Psychiatry, Kang Nam General Hospital (YMS), Seoul, Korea, and Yong-ln Psychiatric Institute Kyunggido, Korea (CEK, HSC). Address reprint requests to Doh Kwan Kim, MD, D,:partment of Psychiatry, Box 3414, l)11keUniversity Medical Center, Durham, NC 27710. Received October 25, 1991; revised March 1, 1993. © 1993 Society of Biological Psychiatry

relevant from the irrelevant is not made on the simple or physical characteristics of the incoming stimuli but rather on the processed assessment of their importance (Posner 1978; Callaway and Naghdi 1982). Interestingly, these LCCPs can be identifiable with the orienting response (OR). Several studies have identified the OR with the allocation of LCCPs (or with the call for such processes), operating only after the activation of preattentional automatic processes (Dawson et al 1982; Packer and Siddle 1989). The electrodermal response is a component of the OR, and as such it is believed to indicate a "call" for processing resources in a central capacitylimited information processing channel when the individual is confronted with uncertain, potentially significant stimuli (Ohman 1979; Bernstein 1981). This electroderrnal response reflects activation of the sympathetic nervous system and is mediated by changes in the electrical conduc0006-3223/93/$06.00

SCOR and Chronic Schizophrenia

tivity of the skin (Edelberg 1972). Therefore, some characteristic cognitive dysfunctions of schizophrenic patients might be reflected by the phasic change in skin conductance following a novel innocuous nontask stimulus of moderate intensity (orienting stimulus). After considerable controversy regarding the replicability of electrode~mal findings, recent reviews (Ohman 1981; Dawson and Nuechtedein 1984; Bemstein 1987; Erlenmeyer-Kimling 1987; Holzman 1987; Dawson et al 1992) as well as cross-laboratory comparisons using standardized methodology (Bemstein et al 1982) have agreed that there are large subgroups of schizophrenic patients who fail to show a skin conductance orienting response (SCOR). Usually between 40%-50% of schizophrenic patients fail to give SCORs to orienting stimuli, compared to only 5%-10% of the normal population. Given these relatively consistent findings on electrodermal nonresponsiveness in schizophrenics, the comparison of electrodermal responders and nonresponders might offer a potentially useful classification scheme. The purpose of the present study was (1) to examine the correlation of cognitive dysfunction as measured by electrodermal responsiveness with clinical neuropsychological testing, and (2) to investigate the characteristics of a subgroup of chronic schizophrenic patients delineated by electrodermal nonresponsiveness. We measured the electrodermal activity with the orienting stimuli of 15 pure tone (1000 Hz, 70 dB, 1 see) sounds followed by one narrow band noise in 31 male chronic schizophrenics and 20 normal controls. We then investigated the associations of neuropsychological impairments, severity of psychopathology, and structural abnormality of brain with the electrodermal responsivenss. Materia!s and Methods

Subjects Thirty-one male psychiatric inpatients at Yong-In Mental Hospital in Kyunggido, Korea, suffering from chronic schizophrenia according to DSM-II1-R criteria (American Psychiatric Association 1987) entered the study. Diagnostic assessments were made by consensus diagnoses independently performed by two board-certified psychiatrists, following a thorough diagnostic interview based on the Diagnostic Interview Schedule (Robins et al 1981). In addition, a significant other was interviewed to provide further objectivity to the diagnoses. The duration of illness of the all patients was more than 5 years (12.2 "4- 5.3 years) with at least 2 years of cumulative hospitalization (7.3 + 3.5 years). The patients were receiving a single antipsychotic medication (chlorpromazine, loxapine, trifluoperazine, or haloperidol). The current mean chlorpromazine-equivalent dosage of neuroleptic medication was

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695.2 mg (SD = 556.1 mg, range = 200--2500 mg). All patients were removed from antiparkinsonian agents with anticholinergic activity at least 1 week prior to electrodermal testing, with the exception of diazepam, which were used as needed. Twenty healthy male volunteers, wP,h no psychiatric history and a normal profile on the Minnesota Multiphasic Personality Inventory (MMPI) Test were studied. The patients and normal controls were matched by age (33.0 -+ 6.3 versus 33.9 ± 5.4 years). Informed written consent to perform the study was given by all patients and volunteers. All subjects passed an audiometric screening examination with pure tone sounds (1000 Hz, 18 dB, 1 see) generated by an avdio signal generator.

Procedure Skin conductance was obtained unilaterally from the palmar surface of the nonpreferred hand using Ag/AgCI electrodes (8 nun in diameter, 5020487, Nihon Kohden, Tokyo) in conjunction with adhesive masks (25 mm in diameter). The external electrolyte was the electrode paste of 0.05 M NaCI solution. Skin conductance was obtained by applying a constant 500 mV across each pair of electrodes, following the instructions provided by Lykken and Venables (1971). All recordings were made on a Nihon Kohden 4300 Polygraph via a Nihon Kohden 2100 GSR detector. Auditory stimuli were generated by a Beltone 200-C clinical audiometer, and delivered binaurally over voltage-calibrated headphones. At the beginning of the session, subjects were asked to perform a breathing exercise, followed by a 5-min relaxation period during which tonic electrodermal activity was measured. The orienting stimuli were one burst of narrow band noise following 15 pure tones (1000 Hz, 70 dB, I sec), with, 15-msec rise time presented at h"rcgular intervals ranging from 30 to 90 sec.

Scoring of Electrodermal Data Tonic skin conductance level (SCL) was assessed by calculating mean skin conductance level sampled each minute (Stephenson and Siddle 1976), and spontaneous fluctuations (SFs) were quantified by counting the total number of deflections exceeding 0.01 izmhos in the last 60 sec before the first orienting stimulus (Siddle et al 1980). The SCOR was defined as an artifact-free phasic change of at least 0.01 izmhos and characteristic shape occurring 1.0-2.4 see poststimulus onset (Levinson et al 1984; Levinson and Edelberg 1985). The trials to habituation score was the trial number of the last pure tone prior to a set number of no-response trials with a two-trials criterion (Levinson and Edelberg 1985). Eleetrodermal nonresponders were defined as those subjects who failed to give an SCOR on

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HABITUATION SCORE OF SCOR

the first three trials (Bemstein et al 1982). Fast habituators were those who gave only one or two responses before habituation (Patterson 1976).

(TWO-TRIAL CRITERION)

50

i

40 ' l

Ratings of Psychiatric Symptoms Severity of psychiatric symptoms was rated by the Brief Psychiatric Rating Scale (BPRS, Overall and Gotham 1962), the Scale for the Assessment of Positive Symptoms (SAPS, Andreasen 1983), and the Scale for the Assessment of Negative Symptoms (SANS, Andreasen 1984). These scales permit the rating of hldi,:'~du~ posi:'v~ ~-,d negative schizophrenic symptoms as well as global psychiatrif symptoms. Our interrater reliability based on Pearson's r was 0.81 for the BPRS, 0.88 for the positive symptoms, and 0.79 for the negative symptoms on a subsample of the patients.

Neuropsychologica! Measurement Neuropsychological tests consisted of the Korean Wechsler Intelligence Scale (KWIS) and Bender Gestalt test (BGT). The degree of cognitive deterioration of each schizophrenic patient was presented by Gonen's deterioration quotient, which is an inverse index of cognitive deterioration by using a hold-don't hold discrepancy, calculated by subtests of the KWIS (Gonen 1970). The degree of perceptual deficit was reflected by the z score in the BGT (Pascal and Suttell 1951). Gonen's D.Q. = (Vocabulary + Information) - (Digit symbol + Block _design) Vocabulary + Information

Computed Tomographic Measurement The scans had a 320 x 320 matrix, and were recorded on transparencies as well as stored by computer. Cuts were obtained at an angle of 15° above the orbitomeatal line and were recorded at intervals of l0 mm, and most scans had 10-12 cuts. Measurements of ventricular and brain size were obtained according to the method provided by Andreasen et al (1982).

[] SCHIZOPHRENICS

% OF SUBJECTS

10 o 0"

0

1

2

3

4 5 6 7 8 9 10 11 12 l"t 14 15 TRIALS TO HABITUATION

Figure 1. Distribution of number of trials to habituation for the total schizophrenic and ¢eatrol groups during the orienting stimuli series.

nonresponding was much higher in the schizophrenics than in normals (48.4% versus 15.0%, X2 = 4.56, p < 0.05). DISTRIBUTION O F S C O R IN H A B I T U A T I O N SERIES. For the total number of trials, the distribution for the chronic schizophrenic patients is skewed with the modal frequency at 0 trial (i.e., nonresponsiveness) as shown in Figure 1. Significantly more patients (58.1%) than controls (20.0%) were at either extreme (nonresponding/nonhabituating) of the trials to habituation distribution for the tone (X2 = 5.71, p < 0.05). And 11 patients (68.8%) out of 18 responding schizophrenics were classified as fast habituators in the habituation stimuli series, there were no fast habituators in 17 normal responders (X2 = 17.53,p < 0.001). TONIC E L E C T R O D E R M A L A C T I V I T Y . T h e patients showed fewer SFs than normal controls [5.05 __ 2,24 versus 15.83 ± 14.54, Fo_,49) = 6.11, p < 0.05], and nonresponding patients displayed many fewer SFs than responders [0.95 _ 1.52 versus 8.90 ___ 4.03, F,,29) = 9.86, p < 0.01]. There were no overall differences between the patients and controls in tonic SCL, but nonresponding patients had significantly lower tonic SCL than responders [8.53 __ 6.55 versus 12.96 __ 8.36 p,mhos, F,.29) = 4.41, p < 0.05].

Results Results on Phasic and Tonic Electrodermal Activities PAIrtfRNS

OF

ELECTRODERMAL

RESPONSIVENESS.

The chronic schizophrenic patients in this study were divided relatively evenly into responders (51.6%) and nonresponders (48.4%), according to their electrodermal responsiveness to orienting stimuli. The incidence of

Comparison of Demographic and Clinical Characteristics between Responding and Nonresponding Schizophrenics There were no overall differences between responding and nonresponding patients in the variables of age, education, age of onset, duration of illness, total length of hospitalization during the lifetime, and frequency of hospitalization (Table 1).

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Table !. Results on Demographic and Clinical Characteristics of Schizophrenic Subjects

Table 2. Results on Neuropsychological Measurements for Schizophrenic Subjects

Schizophrenics (n = 3 0 Responders (n = 16) Characteristic

Mean

SD

Age (Yr) 34.3 7.0 Education (Yr) 12.2 3. I Age of onset (Yr) 22.0 4.9 Duration of t|lness (Yr) 12.3 5.8 Total length of 92.6 48.5 hospitalizationa Frequency of hospitalizationb 4.5 3.1 Medication in CPZ 644 690 equivalents

Schizophrenic subjects (n = 27)

Nom'esponders (n = 15)

Responders (n = 15)

Mean

SD

t

31.6 11.3 19.5 12.1 82.2

5.3 2.8 3.6 4.7 33.5

1.22 0.86 1.66 0.09 0.70

4.0 750

! .9 382

0.55 -0.53

Nonresponders (n = 12)

Variable

Mean

SD

Mean

SD

TIQ (KWlS) c Gonen's D,Q. d z score in BG'P"

102.3 0.13 75.4

I ! .0 0.16 26.0

83.2 -0.06 100.1

t7.4 0.30 36.4

3.42 b 2.03 ~ -3.39 b

°p < 0.05. ~p < 0.01. :Total Intelligence Quotient in the Korean Wechsler Intelligence Scale. aGonen's deterioration quotient, which is an index of cognitive deterioration (see Methods). :The ~orc ix, the Bender Gestalt Test that reflects the degree of perceptual deficit.

OTotal number of months hospitalized during the lifetime. ~Total number of admissions during the lifetime.

To examine the effect of neuroleptic medication on the electrodermal responsiveness, the patients were divided into two groups based on whether they were receiving a neuroleptic with high (ehlorpromazine) or low antieholinergic activity (loxapine, trifluoperazine, haloperidol). The ×2 analysis for the proportion of nonresponders was not different between these two groups (X2 = 1.99, p = 0.15). And there was no difference between responders and nonresponders on chlorpromazine-equivalent dosage of current neuroleptic medication (644 ___ 690 mg versus 750 _ 382 mg, t = 0.53, p = 0.60, Table 1).

Relationship of Electrodermal Responsiveness and Clinical Neuropsychological Testing in Chronic Schizophrenics Nonresponders had lower total intelligence quotient (TIQ, t = 3.42, p < 0.01, more perceptual deficits (t = 3.39, p < 0.01), and lower Gonen's deterioration quotient (t = 2.03, p < 0.05) than responders (Table 2). Logistic regression analysis cff the relationship between a dichotomous electrodermal responsiveness and clinical tteuropsycho!ogicaA measurements revealed that there were significant associations between the electrodermal responsiveness and the variables of TIQ (r = 0.42, model X2 = 10.02, p < 0.005) and Gonen's deterioration quotient (r = 0.23, model X2 = 4.51, p < 0.05). The z score in the BGT revealed no significant association with electrodermal responsiveness.

Comparison of Psychiatric Symptoms between Responding and Nonresponding Schizophrenics Compared to the responding chronic schizophrenic group, the nonresponding group had significantly higher total scores

in the BPRS (t = 2.20, p < 0.05), SANS (t = 2.17, p < 0.05), and SAPS (t = 2.54, p < 0.05) (Table 3). Nonresponders showed higher scores than responders on the "thought disturbance" (t = 2.36, p < 0.05) and "anergia" (t = 2.10, p < 0.05) clusters in the BPRS, and on the "affective flattening" (t = 2.24, p < 0.05), "alogia" (t = 2.45, p < 0.05), "inattentiveness" (t = 2.48, p < 0.05), and "formal thought disorder" (t = 2.95, < 0.01) subsets of the SANS and SAPS.

Comparison of Computed Tomographic Measurements between Normal Controls, Responding, and Nonresponding Schizophrenics In comparison with normal controls, the chronic schizophrenic patients had significantly larger mean ,,entricular brain ratio (VBR) (t = 2.28, p < 0.05) and third ventricle (t = 3.24, p < 0.01). Nonresponding schizophrenics had significantly larger mean VBR [F(2.47) ~- 4.13, p < 0-051 and third ventricle IFt2.47~ = 4.90, p < 0.05] than normal controls, but reeponders did not show any significant differences (Table 4). Ht, wevcr, the variables of area of lateral ventricle, ratio of left to right lateral ventricle, and maximum diameter of fourth ventricle were not different between any two groups.

Discussion The electrodermal abnormalities in the present sample of chronic male schizophrenic patients were generally consistent with both the phasic and tonic aspects of the previous consensus in the literature. First, the distributions of phasic electrodermal activity were similar to those from other reports (Patterson 1976; Ohman 1981; Bernstein et

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Table 3. Results o n Ratings of Psychiatric Symptoms for Schizophrenic Subjects Schizophrenic subjects (n = 31) Responders (n = 16) Variable

Nonresponders (n = 15)

Mean

SD

Mean

SD

35,8 9.9 6.9 7.9 6.4 4.7

i 1.8 3.9 3.3 4.8 2.6 0.9

45.7 9. I 9.8 12.4 8.3 6.1

13.3 3.2 4.5 5.7 3.3 2.4

- 2.20* 0.58 - 2.10. - 2.36 ° - 1.87 - 2.03

Scale for the Assessment of Negative Symptoms Total score 7. I Affective flattening 1.2 Alogia 0.9 Avolition & Apathy I.° Anhcdonia & Asociality 2.1 Inattentiveness 1.2

4.6 1.1 0.8 !4 1.2 1.0

I 1.3 2. I 2.0 2. I 2.8 2.3

6.1 1.2 1.5 1.2 1.3 1.5

-2.17 ~ - 2.24 ~ - 2.45 ° -0.66 -l.64 - 2.48 °

Scale for the Assessment of Positive Symptoms Total score 3.9 Hallucination 1.1 Delusion 1.3 Bizarre behavior 0.5 Formal thought disorder 1.1

4.4 ! .6 1.1 0.8 1.4

8.3 2,3 2.2 1,2 2.7

5.4 1.8 1.5 1.1 1.6

Brief Psychiatric Rating Scale Total score Anxiety-Depression Anergia Thought disturbance Hostility Activation

-

2.54

-

1.97

-

1.99

-

1.97

°

- 2.95 ~

°p < 0,05. bp < 0.0l.

T a b l e 4. R e s u l t s o n C o m p u t e r i z e d T o m o g r a p h i c a l M e a s u r e m e n t s Schizophrenic subjects (n = 31)

Controls (n = 19)

Responders (n = 16)

Nonmsponders (n = 15)

Variable

Mean

SD

Mean

SD

Mean

SD

VBR b LV/RV ~ Third V d Fourth V e

6.70 ~ 1.10 4.88 a 16.23

1.84 0.18 1.25 2.19

7.38 1.10 6.08 16.78

1.97 0.34 2.27 3.17

8.69 ~ 1.29 6.9Sw 16.84

2.26 0.38 2.33 2.07

~ n o t e s pairs of groups significantly different at the 0.05 level. bVentricular brain ratio (%): Area of lateral ventricle/Area of brain x 100. ~Area of left lateral ventricle/Area of right lateral ventricle. #Maximum diameter of 3rd ventricle (ram). 'Maximum diameter of 4th ventricle (ram).

al 1982; Dawson and Nuechterlein 1984; Levinson et al 1985; Green et al 1989) with a much higher incidence of nonresponding among patients than among controls (48.4% versus 15.0%) and a more prevalent fast habituating pattern of patients than controls (68.8% versus 0%). Second, the nonresponding schizophrenic subgroup showed lower levels of tonic electrodermal activities (SCL, SFs) than responding patients, and among responding schizophrenics SFs were even higher than normal controls. These results are also consistent with the previous consensus (Spohn and Patterson 1979; Bernstein et al 1982; Dawson and Nuech-

terlein 1984; ttolzman i987, Ohraar. ct aI !989) Ra,~ed on these findings, we turn to the relationship of these abnormalities with cognitive dysfunction measured by clinical neuropsychological tests. In terms of cognitive functioning, nonresponders had lower intelligence quotients and were more deteriorated than responders. There ~ere sigr/leant associations between the electrodermal responsiveness and the variables of TIQ and Gonen's deterioration quotient. These findings strongly support the hypothesis of psychophysiologic measurement of electrodermal activity as a general indicator

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of impaired cognitive status in chronic schizophrenic patients (Ohman 1979; Bemstein 1981). However, we cannot state from the present data whether the observed relationship between electrodermal responding and neuropsychologic impairment applies only in chronic schizophrenic patients. Data from normal control subjects and from other psychiatric comparison groups (e.g., affective disorder) would be necessary to answer this question. If we consider the deviant orienting response in chronic schizophrenics to be an indicator of a very general and fundamental dysfunction in the underlying psychophysiological systems (i.e., inadequate arousal modulation in response to incoming stimuli), then we should also expect to find the electrodermal nonresponsive pattern reflected in clinical features. The variables of age, education, age of onset, duration of illness, life-time length of hospitalization, and frequency of hospitalization did not differentiate the two patient groups defined by the phasic electrodermal activity. Also, the anticholinergic activity of neuroleptic medication did not affect the electrodermal responsiveness in this study. These findings suggest that electrodermal nonresponding reflects the current psychopathological condition in chronic schizophrenic patients, as other investigators have noted (Gruzelier and Venables 1972; Ohman 1981; Zahn et al 1981b). In terms of psychopathology, nonresponders had more severe thought disturbance and deficit symptoms than responders, in agreement with other studies (Straube 1979; Bernstein et al 1981). However, we did not find distinct symptom profiles for elec:rodermal responders and nonresponders. Nonresponders showed more psychiatric symptoms overall, rather than more negative symptoms, as indicated by the apparently significant differences for total scores in the SAPS and BPRS as well as the SANS. Our data are more consistent with those of Aim et al (1984) and Green et al (1989) who reported more positive and negative symptomatoiogy in nonresponders. These findings suggest that electrodermal nonresponding might be also considered as a general indicator of cross-sectional symptom severity in chronic schizophrenia. Compared to controls, the chronic schizophrenic patients in this study also showed third ventficular enlargement and reduction in relative cortical volume (increased VBR), as ~ t ~ ~t.her studies (Shelton and Weinberger 1986; Raz and Raz 1990). Furthermoic, ~,e found these structural brain abnormalities were more apparent m the electrodermal nonresponding schizophrenic subgroup. Third ventricular enlargement may involve damage to the surrounding areas with an excitatory role in electrodermal activity, such as the anterior hypothalamus, amygdala, and :~tid!'-'.-_c nucleus of the thalamus (Wang 1964, Barr 1979). Whether such damage actually exists, and if so, which areas are affected, cannot be determined from the present data. How-

ever, these results support the hypothesis of Cannon et al (1988) that third ventricular enlargement may be associated with reduced autonomic nervous system activity. .,Mthough it is not certain what it costs the schizophrenic nonresponder to be nonresponsive, SCOR nonresponse might reflect an ailocational decision. Previous studies (Bemstein et al 1980, 1985; Gmzelier et al 1981) suggest that the schizophrenic deficit occurs at the point in the attentional process in which stimuli are weighed for significance and the decision is made whether to engage central attentic~fl mechanisms, rather than in loss of detection, filtering, or OR capability, per se. We have found a consistent combination of data that show an association of electrodermal nonresponsivity with greater neuropsychological abnormalities in chronic schizophrenic patients. First, electrodermal nonresponsiveness was correlated with the cognitive deterioration measured by clinical neuropsychological tests. Second, the tonic electrodermal data might indicate that nonresponding chronic schizophrenics had a lower arousal level than responders. Tonic electrodermal activity is well known to reflect sympathetic arousal level, as demonstrated by experiments with amphetamine and threat of electric shock (Bohlin 1976; Zahn et al 1981a). Third, the overrepresentation of structural brain abnormality among nonresponding schizophrenics also supports this association indirectly. Our data of computerized tomographic (CT) measurements are concordant with those of Cannon et al (1988), who reposed that lowered electrodermal response in the early teens in high-risk children was related to enlarged third ventfcles in adults succumbing to schizophrenia. In several theoretical review articles it has been concluded that there appears to be a relationship between CT abnormalities of the brain and cognitive deficits in schizophrenic patients (Seidman 1983; Weinberger 1984; Zec and Weinberger 1986). In conclusion, electrodermal nonresponding in chronic schizophrenic illness might be considered as a functional index associated with greater neuropsychological abnormalities and more severe symptoms. Furthermore, those patients who had structural abnorm,ality of br~n were overrepresented among electrodermal nonresponding schizophrenics. If subsequent research can establish that these findings are reliable, the distinction between electrodermal responders and nonresponders might offer a potentially useful dimension of subtyping patients with chronic schizophrenia. The authors would !~kc to thank Dr. Bernard J Carroll, Department of Psychiatry, Duke University Medical Center, Durham, NC, for his hC.pf.;l discussion and editorial corrections. Thig work was supported by a research grant from Yong-ln Psychiatric Institute (1989), and was presented at 5th World Congress of Biological Psychiatry on June 12, 1991.

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