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Marked Clozapine-Induced Slowing of EEG Background Over Frontal, Central, and Parietal Scalp Areas in Schizophrenic Patients

Joutsiniemi, Sirkka-Liisa*; Gross, Andres; Appelberg, Björnand †

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Journal of Clinical Neurophysiology: January 2001 - Volume 18 - Issue 1 - p 9-13
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It is known (Spatz and Kugler, 1981) that many drugs change the frequency content of EEG. Benzodiazepines increase mainly fast-frequency activity whereas neuroleptics increase the amount of slow-frequency activity. These observations were made at the time of paper EEG devices, on the basis of visual evaluation of the signal. The digitally recorded EEG, the ability to measure EEG simultaneously over the entire scalp, and mathematical analytic methods make it possible to study and to compare not only the numeric values of the spectral content but also the topographic patterns of it. One goal of EEG research in psychiatry is to develop analyzing methods to provide a tool that follows the course of the disease and the effects of therapy. However, the obligatory prerequisite for this goal is first to define quantitatively and topographically typical EEG changes for different drugs.

Clozapine is known as an atypical neuroleptic drug that is effective in treatment-resistant schizophrenia. It affects both negative and positive symptoms, and does not have the typical extrapyramidal side effects. However, it is also known to give rise to epileptiform disturbances as well as disturbances in the background activity on EEG (Guenther et al., 1993; Nousiainen et al., 1991; Risby et al., 1993; Tiihonen et al., 1991). Small et al. (1987) studied the topographic changes in background EEG activity caused by haloperidol, chlorpromazine, and clozapine. According to their results, both clozapine and chlorpromazine used as monotherapy increases the θ power on the frontal scalp areas. So far, their results have not been reproduced.

The frequency and often misleading prominence of the visually detected EEG changes in patients treated with clozapine have impressed us during our clinical work. Because the slowing of EEG readings of clozapine-treated patients seemed to differ from that of nonclozapine-treated patients, we decided to analyze quantitative and topographic differences in the spectral contents of the EEG between these groups.



Forty-two inpatients with schizophrenia or schizoaffective disorder were included in the study. All inpatients in Tammiharju Mental Hospital who had chronic schizophrenia or schizoaffective disorder, and who were able to participate and willing to give informed consent, were included in the study. Diagnoses were made using the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised, criteria (American Psychiatric Association, 1987) by two psychiatrists. Patients with any organic brain lesion, anamnesis of heavy alcohol or drug abuse, concomitant neurologic illness, organic psychosis, or other delusional disorders were excluded. The patients were informed of the aim and course of the study, and they gave their written consent. The study was approved by the local ethics committee.

The control group was comprised of healthy volunteers from the staff of the hospital without any neurologic or psychiatric disease in the anamnesis. This group consisted of 29 subjects, none of whom was medicated. The male-to-female ratio was 8:21 and the mean age was 35 years (age range, 21–56 years).

Patients are presented in two groups: the nonclozapine-treated group and the clozapine-treated group, with 21 patients in each group. The nonclozapine-treated group consisted of patients diagnosed with schizophrenia disorganized type (n = 3), schizophrenia paranoid type (n = 11), schizophrenia residual type (n = 5), and schizophrenia undifferentiated type (n = 2). The average duration of illness was 13.7 years (range, 4–41 years), the duration of neuroleptic treatment was 13.2 years (range, 1–37 years), and the male-to-female ratio was 8:13. The average age was 39 years (age range, 28–67 years). Patients were medicated with one to three neuroleptic drugs: Chlorpromazine, zuclopenthixol, haloperidol, molindone, thioridazine, chlorprotixen, levomepromazine, flupenthixol, perphenazine, zotepine, and sulpiride were used. The average dose, calculated as chlorpromazine equivalents, was 405 mg (range, 80–1,050 mg). Some patients who responded poorly to treatment were treated additionally with carbamazepine (n = 3) and valproate (n = 1).

The clozapine-treated group consisted of 21 patients diagnosed with schizophrenia disorganized type (n = 9), schizophrenia paranoid type (n = 6), schizophrenia residual type (n = 1), schizoaffective-type psychosis (n = 3), and schizophrenia undifferentiated type (n = 2). The average duration of illness was 15.7 years (range, 3–27 years), their duration of neuroleptic treatment 15.5 years (range, 3–27 years), and the male-to-female ratio was 13:8. The average age was 37.6 years (range, 19–60 years). Patients were treated with a mean dosage of clozapine of 514 mg/day (range, 100–900 mg/day). Additionally, eight patients were treated with another neuroleptic: chlorpromazine, zuclopenthixol, haloperidol, molindone, thioridazine, flupentixol, or risperidone. The average (n = 8) dose by chlorpromazine equivalents was 625 mg. Because of insufficient antipsychotic response, carbamazepine (n = 2), oxcarbamazepine (n = 1), lithium (n = 2), and valproate (n = 3) were also used. These combinations of drugs were those used normally in clinical work in Tammiharju Hospital.

EEG Recording

EEGs were recorded digitally during the years 1993 to 1994 as a part of the clinical work. During recording the subjects were awake with their eyes closed. The EEGs were studied retrospectively.

The standard 10–20 electrode placement system with 21 electrodes on the scalp and one on both earlobes was used in recording. The sampling rate was 200 Hz, with a low-pass limit of 70 Hz, and a time constant of 0.3 second. The digital recordings were saved on optical disks.

Calculating the Results

The topographic quantitative calculations were made using the Cadwell Spectrum P32 Neurometrics program (Cadwell Laboratories, Kennewick, WA) using linked ears as a reference. The digitally recorded EEGs were screened visually, and 48 2.5-second artifact-free epochs were selected from the typical background of the awake subject for subsequent analysis. As a result of the fast Fourier transformation (FFT), the averaged spectral power values of the δ (1.5–3.0 Hz), θ (3.0–7.5 Hz), α (7.5–12.5 Hz), and β (12.5–20.0 Hz) bands were produced separately for each of the 21 scalp electrodes.

The power values of different frequency bands at each electrode location were compared statistically between the clozapine-treated group, the nonclozapine-treated group, and the healthy subjects. Because of skewed distributions, the nonparametric Kruskal–Wallis test and Spearman’s rank correlation coefficient were used. Significance was set at P = 0.001.


The statistical frequency distributions of the absolute power values of different bands in all groups were skewed (Fig. 1). There was no significant difference at any electrode in either the α power or the β power distributions between the groups (see Figs. 1A and 2). There was no statistical difference in the δ, θ, α, or β power values between the two hemispheres in any group. Figure 3 illustrates the distributions of the α power values for each group and hemisphere. The main difference between the clozapine-treated group and the other groups was the wider range of absolute θ power values in the clozapine-treated group compared with the healthy subjects and the nonclozapine-treated group (see Fig. 1B). The greatest difference in θ power values was observed on the anterior and centroparietal areas of the scalp.

FIG. 1
FIG. 1:
(A, B) Frequency distribution of the absolute power values of the α (A) and θ (B) band of the background EEG activity at four electrode locations (Fz, C3, C4, and Pz) in the clozapine-treated and nonclozapine-treated groups (n = 21 each) and healthy subjects (n = 29). The y-axis shows the count of subjects; the x-axis shows the absolute power value in microvolts squared.
FIG. 2
FIG. 2:
The y-axis shows the average power values in microvolts squared of different frequency bands at midline electrodes for the clozapine-treated and the nonclozapine-treated groups (n = 21 each), and the healthy subjects (n = 29). The insert shows the locations of the electrodes on the scalp.
FIG. 3
FIG. 3:
The y-axis shows the average power values in microvolts squared of different frequency bands at electrodes on both hemispheres in the clozapine-treated and the nonclozapine-treated groups (n = 21 each) and the healthy subjects (n = 29). The insert shows the locations of the electrodes on the left hemisphere, which have odd numbers in their names. The respective electrode names on the right hemisphere include the next even number. For example, the occipital electrode 01 on the left has its counterpart 02 on the right hemisphere.

The mean θ and δ power values were higher in the clozapine-treated group than the nonclozapine-treated or healthy groups (see Fig. 2) in all electrodes. Statistical testing suggested highly significant differences (P < 0.001) in the θ power values on the frontal and central areas between the clozapine-treated and the nonclozapine-treated groups. There was no significant difference between the clozapine-treated and the nonclozapine-treated groups in the parietal or occipital electrodes.

Significant differences in θ power value were observed between the clozapine-treated group and the healthy group. There was no difference between the nonclozapine-treated group and the healthy group, which was also seen in the visual evaluation of the distributions (see Fig. 1).

On the posterior areas, the differences between the groups were similar to those of the anterior areas, although not always significantly. The clozapine-treated group and the healthy group differed from each other significantly at every electrode location, whereas the nonclozapine-treated and the healthy groups did not differ.

Comparing the patient groups, there was a significant difference between the θ power values at a single posterior electrode (O2) only; otherwise, the groups did not differ significantly from each other.

The δ power distribution behaved similarly to that of the θ power (see Figs. 2 and 3). There was a significant difference (P < 0.001) in the δ power values between the clozapine-treated group and the other groups on anterior scalp areas. On posterior areas, the healthy group and the clozapine-treated group differed significantly from each other at every electrode. However, there was also some increase of the δ power in the nonclozapine-treated group. Between patient groups, the difference in the δ power values was not significant at the most posterior electrodes: 01, 02, Oz, Pz, and T5. The δ power values of the healthy group and the nonclozapine-treated group differed from each other significantly at only one electrode (Oz).

To rule out the effect of chlorpromazine, which is known to slow EEG readings in anterior and central areas, we omitted those patients (four patients in the clozapine-treated group and three patients in the nonclozapine-treated group) who received it, and repeated the statistical comparison for the central electrodes Cz, C4, and C3. The difference between the groups remained highly significant. A similar procedure was performed for carbamazepine and lithium, and the differences between the patient groups remained significant. We also compared the θ values of the patients receiving clozapine as the only neuroleptic (N = 13; seven male patients and six female patients) with the patients on other neuroleptics except clozapine. The difference remained significant (P < 0.001) for all electrodes except for electrodes P3, O2, T5, Fpz, and Oz (P < 0.01). A positive, although not significant, correlation between θ power and daily doses of clozapine was also found for all electrodes, varying between r = 0.591 (P = 0.034, Fz) and r = 0.344 (P = 0.249) in these 13 patients.

No gender differences were observed in the group of patients receiving clozapine together with other neuroleptics. P values for all electrodes were more than 0.4.


Quantitative EEG analysis may, when used properly, be a useful diagnostic tool in some central nervous system disorders (Nuwer, 1997; Prichep and John, 1992). In our work, the topographic features of the slowing differentiated the groups from each other. The increased amount of θ and δ activity was widespread but emphasized the central anterior and most parietal areas in the clozapine-treated group. Small et al. (1987) reported similar topographic EEG changes in θ amplitude during pure clozapine treatment. Our results confirm their observations and also provide new information for practical situations. In clinical every-day work, patients are treated with several drugs simultaneously. The topographic features caused by clozapine are detectable during different combinations of drugs.

According to Small et al. (1987), chlorpromazine also slows EEG readings on the central and anterior scalp areas. In our work the slowing was not explained by chlorpromazine. Carbamazepine and lithium are also known to slow EEG readings, but none of these explained our results and, omitting the eight patients who received clozapine together with other neuroleptics, did not affect the results. Because our patients’ medication consisted of several different drugs simultaneously, there may be, in addition to a pure clozapine effect, additive and counteracting interactions that affect the electrical activity, but the purpose of this study was not to detect them.

The healthy group and the nonclozapine-treated group did not differ from each other except in δ power value at a single posterior electrode (Oz). In addition, there were no significant differences between the power values of the two hemispheres in different groups. Morstyn et al. (1983) have reported both increased θ and δ on frontal areas, and increased β on the left anterior temporal area in medicated patients with schizophrenia compared with healthy control subjects. These differences are probably small compared with the remarkable slowing and differences caused by clozapine. The current nonparametric method of statistical comparison, and the high significance level that we used, are suboptimal for revealing small statistical differences.

The slowing of EEG readings, caused by medication, is often detected on the posterior areas of the scalp. In the rat, clozapine is known to affect neurotransmission preferentially in the mesocorticolimbic system, including the medial prefrontal cortex (Wang et al., 1994; Yamamoto et al., 1994). The slowing of EEG readings on the frontal and midline areas during clozapine treatment may reflect changes of electrical activities in these areas. Thus, EEG research may have some contribution in elucidating mechanisms of action of psychoactive drugs. Studies to determine how EEG changes correlate with the clinical effect, and side effects, are needed.


The authors thank EEG nurse R. Isotalo–Rahkonen for her expert technical help and chief physician Dr. K. Palmgren for his support of this study.


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Schizophrenia; Quantitative EEG; Clozapine; Traditional neuroleptics.

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