Article

EEG Abnormalities During Treatment

With Typical and Atypical Antipsychotics

Franca Centorrino, M.D.
Bruce H. Price, M.D.
Margaret Tuttle, M.S.
Won-Myong Bahk, M.D., Ph.D.
John Hennen, Ph.D.
Matthew J. Albert, B.A.
Ross J. Baldessarini, M.D.
Objective: Clozapine produces EEG ab-
normalities and dose-dependent risk of
epileptic seizures. Much less is known
about EEG effects of newer antipsychotics.
The present study therefore examined the
risk of EEG abnormalities associated with
various antipsychotic drugs.
Method: EEG recordings from 323 hospi-
talized psychiatric patients (293 treated
with antipsychotics, 30 who did not re-
ceive any antipsychotic treatment) were
graded blind to diagnosis and treatment
for type and severity of EEG abnormalities.
Drug type, dose, and clinical factors were
evaluated for association with EEG abnor-
malities by multivariate logistic regression.
Results: EEG abnormalities occurred in 56
subjects (19.1%) treated and four (13.3%)
not treated with antipsychotics. EEG ab-
normality risk among antipsychotic agents
varied greatly (clozapine=47.1%, olanza-
pine=38.5%, risperidone=28.0%, typical
neuroleptics=14.5%, quetiapine=0.0%).
Significant risk factors in order of influence
were hypertension, use of an atypical anti-
psychotic, bipolar diagnosis, and older
age; benzodiazepine cotreatment lowered
risk. Unassociated with risk were sex, treat-
ment response, length of hospital stay,
drug potency, daily dose (in mg or mg/kg),
drug exposure time, or cotreatments.
Conclusions: EEG abnormality risk varied
widely among specific antipsychotics. Risk
was particularly high with clozapine and
olanzapine, moderate with risperidone
and typical neuroleptics, and low with
quetiapine. Comorbid hypertension, bipo-
larity, and older agebut not dose or clin-
ical responsewere associated with risk.

(Am J Psychiatry 2002; 159:109115)

E lectroencephalography was introduced by Hans

Berger of Jena, Germany, in 1929, primarily to study brain
dysfunction in mental illnesses (1). The initial hope that it
would either lead to specific knowledge of cerebral patho-
physiology or support differential diagnosis in idiopathic
major mental illnesses has long been abandoned. Never-
theless, it continues to have value in the diagnosis of epi-
lepsy, brain damage, delirium, and dementia and in differ-
entiating brain disease from primary psychiatric disorders
(2, 3). Electroencephalographic (EEG) abnormalities oc-
cur in patients with various idiopathic psychiatric disor-
ders. In studies antedating widespread use of modern
atypical antipsychotic agents, about 30% of hospitalized
psychotic patients had EEG abnormalities over the tem-
poral lobes (4), with epileptiform EEG abnormalities in
about 2.6% of cases (5). EEG abnormalities also have been
found in manic patients (6).
Relative contributions of primary brain dysfunction and
effects of medicinal treatments to these EEG findings
largely remain uncertain. Many psychotropic drugs can
alter EEG activity (18). Older neuroleptics commonly
produce excessive diffuse, slow-wave EEG activity or in-
creased alpha rhythm without obvious clinical manifesta-
tions (9, 10). Low-potency neuroleptics can also induce
clusters of slow dysrhythmic waves, sharp waves, or spike
and slow-wave responses that may anticipate overt epi-
leptic seizures (11). EEG abnormalities associated with re-
cently introduced antipsychotic-antimanic drugs have
been minimally studied. Clozapine has an unusually high
impact on EEG activity and has induced a variety of types
of epileptic seizures (12), dose dependently, in about 10%
of patients exposed to a range of clozapine doses (25900
mg/day) for up to 3.8 years (13). Rates of EEG abnormali-
ties during treatment with newer atypical antipsychotics
have been much less well evaluated (7).
Given the limited knowledge of EEG abnormalities
among patients treated with modern antipsychotics, we
undertook an extensive retrospective analysis of EEG re-
cordings of 293 psychiatric inpatients treated with various
antipsychotic agents as well as those of 30 whose treat-
ment did not include these agents. We also considered as-
sociations of EEG findings with selected clinical and treat-
ment factors. We hypothesized that EEG abnormalities
would be associated mainly with atypical antipsychotics
of low potency and would increase with drug dose.
Method
Subjects
Medical records of 2,812 psychiatric patients admitted to
McLean Hospital between January 1992 and February 1999 who
underwent electroencephalography as inpatients were reviewed.
Criteria leading to exclusion of 2,489 (88.5%) of the patients

Am J Psychiatry 159:1, January 2002 109

EEG ABNORMALITIES AND ANTIPSYCHOTICS
screened were age <14 years, epilepsy, cerebral tumor, stroke,
traumatic brain injury without full recovery, clinical or brain scan
evidence of focal brain lesions, current delirium, Downs syn-
drome, current migraine headaches, history of multiple sclerosis,
positive HIV test, any instance of loss of consciousness that ex-
ceeded 5 minutes, prior drug overdose leading to coma, WAIS IQ
<70, prior EEG abnormalities, alcohol and drug abuse or with-
drawal within 10 days of the EEG recording, current anticonvul-
sant treatment (including use of anticonvulsants as mood stabi-
lizers), or receiving ECT within the previous 4 months.
Of the remaining subjects entered into the study, 293 were re-
ceiving antipsychotic treatment. Their mean age was 35.6 years
(SD=15.7, range=1382); 50.5% (N=148) were male. The other 30
patients, who passed the exclusion criteria but who were not re-
cently or currently being treated with an antipsychotic, were se-
lected as control subjects. The mean age of this group was 33.3
years (SD=18.0, range=1569); 43.3% (N=13) were male. They
were required to have had no oral antipsychotic treatment for at
least 5 days and no long-acting injected neuroleptic for at least 2
weeks (if given fluphenazine) or 4 weeks (if given haloperidol) be-
fore their EEG recording. Psychiatric diagnoses (according to
DSM-IV ) among subjects treated and not treated with antipsy-
chotics included schizophrenia/schizoaffective disorder (41.3%
[N=121] and 23.3% [N=7], respectively), bipolar disorder (26.6%
[N=78] and 23.3% [N=7]), and major depression (17.7% [N=52]
and 13.3% [N=4]) along with a miscellaneous category of other
diagnoses (14.7% [N=43] and 40.0% [N=12]).
Data collected from medical records included sex, age, and
handedness; discharge psychiatric and substance abuse diag-
noses (updated to meet DSM-IV criteria by consensus); comorbid
medical and neurological diagnoses; antipsychotic type, current
dose, and duration of use before EEG recording; type and dose of
other drugs used at the time of the EEG recording; length of hos-
pitalization; and treatment response as recorded in discharge
summaries. Antipsychotic drug doses (mg/day) were converted
to chlorpromazine equivalents and corrected (mg/kg) for body
weight (8, 14).
Antipsychotic Treatment
Treatment was categorized by agents used at the time of the EEG
recording. Subjects exposed to more than one antipsychotic (N=
24) were assigned to a combination treatment category. Typical
neuroleptics were categorized as high potency (e.g., fluphenazine,
haloperidol, loxapine, perphenazine, pimozide, thiothixene, triflu-
operazine) or low potency (e.g., chlorpromazine, mesoridazine,
molindone, thioridazine) on the basis of daily dose (i.e., ones or
tens of mg/day versus hundreds). Similarly, atypical agents also
were divided into drugs of high potency (risperidone) and low or
moderate potency (clozapine, olanzapine, and quetiapine).
Seventeen treatment groups were formed comprising 15 indi-
vidual antipsychotic agents, a combination category, and the un-
treated control group. Drug type subgroups were also formed to
compare typical versus atypical and high- versus low-potency
agents.
Outcome Measures
Principal outcome measures were a binary categorization (EEG
abnormality present versus absent) and EEG abnormality sever-
ity scores within the defined treatment groups. Clinical outcome
was also considered in relation to EEG abnormality status on the
basis of condition at discharge rated by consensus assessment of
information in the medical record and clinical discharge sum-
mary. Hospital length of stay was also employed as a surrogate in-
dex of treatment responsiveness.
110
EEG Assessment
EEG recordings (one per subject) were performed according to
recommendations of the American Electroencephalographic So-
ciety, with a standard 10/20 placement of 21 electrode leads; bi-
polar and referential montages were used (15). EEG recordings
during the awake state were obtained from all antipsychotic-
treated patients and control subjects; 62.1% (N=182) of the anti-
psychotic-treated patients and 63.3% (N=19) of the control sub-
jects were also recorded during sleep; drowsiness was noted in
the EEG recordings of 48.1% (N=141) of the antipsychotic-treated
patients and 3.3% (N=1) of the control subjects. Recording during
hyperventilation was obtained from 68.9% (N=202) of the anti-
psychotic-treated patients and 90.0% (N=27) of the control sub-
jects. Photic stimulation was performed in 93.9% (N=275) of the
antipsychotic-treated patients and 96.7% (N=29) of the control
subjects. The original EEG interpretations and reports were gen-
erated by two experienced, board-certified neurologists. A senior
behavioral neurologist (B.H.P.), blind to patients names, diag-
noses, medications, and clinical outcome, reinterpreted and
scored all EEG recordings to assure rating consistency. Reliability
of EEG scoring was tested by blind repeated scoring of 30 ran-
domly selected tracings assessed with the kappa statistic and in-
traclass correlations for blind reproducibility of actual EEG
scores.
EEG activity was scored as follows: 0=no abnormality; 1=mild
abnormality (generalized or frontal symmetrical theta slowing);
2=moderate abnormality (theta and delta slowing, asymmetrical
focal theta or delta, generalized intermixed theta and delta activ-
ity, sharp waves or phase reversal); 3=severe abnormality (spike
discharges or spike-and-wave activity, either alone or with the
characteristics of moderate abnormality). Since only a minority of
EEG recording occurred during drowsiness, when EEG patterns
can be highly variable (16, 17), abnormalities recorded only dur-
ing drowsiness were excluded.
Explanatory Factors
Descriptive factors examined for bivariate correlation with
EEG abnormality included age, sex, and handedness. Clinical fac-
tors similarly examined included primary psychiatric diagnosis,
medical diagnoses, psychosis active at the time of EEG testing,
comorbid substance use disorder, length of hospitalization ad-
justed for year of admission, and overall quality of treatment re-
sponse. Treatment variables considered included use of any anti-
psychotic agent and the specific drug given; cotreatment with an
antidepressant, benzodiazepine (either standing or as-needed
doses), or lithium; mean chlorpromazine-equivalent dose (total
mg/day and mg/kg body weight); and duration of treatment ex-
posure.
Statistical Methods
Factors were organized by natural categories or those created
by use of median-split continuous data to permit use of contin-
gency tables (chi-square) to test for associations with the pres-
ence of EEG abnormalities. Continuous variables were log-trans-
formed when necessary to improve distribution normality.
Factors with suggestive associations (p0.05) with either presence
or absence of EEG abnormalities in the preliminary analyses were
then evaluated by multivariate logistic regression to identify a set
of risk factors related to EEG abnormality (with partial-residual
plots used to check for model fit) and to obtain odds ratios (and
95% confidence intervals [CIs]) for specific comparisons. Regres-
sion modeling with EEG score as the dependent variable was car-
ried out by using ordinal logistic regression modeling methods.
Robust methods were used to obtain standard error estimates. In-
teractions between factors retained in multivariate models were
checked for significance. Goodness-of-fit chi-square tests were
used to check for model fit. Averages are reported as means and
Am J Psychiatry 159:1, January 2002
 CENTORRINO, PRICE, TUTTLE, ET AL.

TABLE 1. EEG Results by Type of Antipsychotic Treatment for 323 Hospitalized Psychiatric Patients
EEG Score Risk of EEG
(0=no abnormality, Abnormality Risk of
Dose (mg/kg/day)a 3=severe abnormality)b (score >0)c Severe EEG
Antipsychotic Regimen N Mean SD Mean SD % 95% CI Abnormalityd (%)
Agents (in order of decreasing risk)
Clozapine 17 3.7 2.5 0.94 1.09 47.1 20.673.5 5.9
Olanzapine 13 2.8 1.2 0.77 1.09 38.5 7.969.1 7.7
Trifluoperazine 11 3.4 1.6 0.64 1.03 36.4 2.570.3 9.1
Mesoridazine 3 1.4 0.6 0.33 0.58 33.3 0.0100.0 0.0
Risperidone 25 4.0 2.0 0.56 0.96 28.0 9.146.9 4.0
Fluphenazine 18 8.0 5.2 0.33 0.69 22.2 0.843.5 0.0
Thiothixene 9 3.3 1.5 0.56 1.13 22.2 0.056.1 11.1
Combination 24 5.9 2.6 0.42 0.88 20.8 3.338.4 4.2
Perphenazine 70 3.1 1.7 0.30 0.70 14.3 5.922.7 1.4
Chlorpromazine 14 3.0 2.1 0.21 0.58 14.3 0.035.3 7.1
Thioridazine 23 2.0 1.3 0.22 0.60 13.0 0.027.9 0.0
Haloperidol 55 3.8 3.0 0.13 0.47 7.3 0.214.4 0.0
Loxapine 4 3.7 3.4 0.00 0.00 0.0 0.0 0.0
Quetiapine 5 2.4 2.0 0.00 0.00 0.0 0.0 0.0
Pimozide 1 7.5 2.00
Molindone 1 0.8 0.00
Type
Typical 214 3.6 2.9 0.27 0.69 14.5 9.719.2 1.9
Atypical 79 4.1 2.3 0.63e 0.99 31.6f 4.242.1 5.1
Potency
High 220 4.0 2.9 0.34 0.79 17.7 12.622.7 2.7
Low 73 3.0 2.3 0.42 0.83 23.3 13.433.2 2.7
All antipsychotics 293 3.8 2.8 0.36 0.80 19.1 14.623.6 2.7
No antipsychotic 30 0.27 0.69 13.3 0.426.2 0.0
a Value in chlorpromazine equivalents; for specific agents, dose data are for subjects given only the indicated antipsychotic.
b For specific drugs given to at least five patients, there was a nonsignificant difference in scores (F=2.19, df=11, 272, p=0.15).
c Significant difference in risk among specific drugs (2=34.7, df=12, p=0.004).
d Spike discharges or spike-and-wave activity (score=3).
e Significantly higher score than that of subjects given typical antipsychotics (2=10.9, df=1, p<0.001).
f Significantly higher abnormality risk than that of subjects given typical antipsychotics (2=11.9, df=1, p<0.001).

standard deviations or with 95% CIs unless stated otherwise.
Results with two-tailed p0.05 were considered statistically non-
significant. Analyses employed Statview (SAS Corp., Cary, N.C.)
and Stata (Stata Corp., College Station, Tex.) microcomputer
programs.
Results
The EEG results by antipsychotic treatment type for the
323 subjects are presented in Table 1. Four atypical agents
were encountered, given alone to 60 patients and in com-
bination with an additional antipsychotic in another 19
(N=79 total, or 27.0%; nine of the combination cases in-
volved clozapine). Eleven different typical neuroleptics
were used, given alone to 209 patients and in combination
with an additional typical antipsychotic in another five. In
all, 24 cases involved antipsychotic combinations: an
atypical plus typical agent in 15 cases, two typical neuro-
leptics in five, and two atypical agents in four. Daily chlor-
promazine-equivalent doses averaged 3.80 mg/kg (SD=
3.02) (or 279 mg/day, SD=222), with a median of 3.10 mg/
kg (or 200 mg/day), ranging from 1.40 mg/kg (mesorida-
zine) to 8.00 mg/kg (fluphenazine).
For the 30 tracings randomly selected for reliability
measurements, ratings of normal/abnormal yielded a
kappa of 0.87 (z=4.79, df=30, p<0.0001), and the EEG
scores had high reproducibility (intraclass correlation co-
efficient [ICC]=0.94, 95% CI=0.900.98; F=31.9, df=1, 29,
p<0.0001). EEG abnormalities (rating score >0) were found
in 19.1% (N=56) of the antipsychotic-treated patients but
also in 13.3% (N=4) of the hospitalized patients not treated
with an antipsychotic (Table 1). This minor overall differ-
ence in risk was not statistically significant (2=0.60, df=1,
p=0.44) nor was the difference in average EEG score (z=
0.74, p=0.46), reflecting a wide range of outcomes among
individual subjects and drugs. Mild EEG abnormalities
(score=1) were found in 8.2% (N=24) of the antipsychotic-
treated patients and in 10.0% (N=3) of the control sub-
jects; moderate ratings (score=2) were found in 8.2% (N=
24) and 3.3% (N=1) of those treated and not treated with
antipsychotics, respectively. Severe EEG abnormalities
(score=3, indicating spike discharges or spike-and-wave
activity) were found in 2.7% (N=8) of the antipsychotic-
treated subjects. In order of risk, severe abnormalities
were associated with thiothixene, trifluoperazine, olanza-
pine, chlorpromazine, clozapine, combination antipsy-
chotic therapy, risperidone, and perphenazine (Table 1).
No patient treated with quetiapine or any other agent
alone received a score of 3, nor did any untreated patient
(Table 1).
Average EEG abnormality ratings varied greatly among
specific antipsychotics (Table 1). Mean scores ranged from
lows of 0.27 (SD=0.69) in the 30 antipsychotic-free sub-
jects (and nil in small groups of five quetiapine-treated

Am J Psychiatry 159:1, January 2002 111

EEG ABNORMALITIES AND ANTIPSYCHOTICS
FIGURE 1. Risk of EEG Abnormalities With Specific Antipsy-
chotic Agents Among 293 Hospitalized Psychiatric Patients
Clozapine
Olanzapine
Trifluoperazine
Mesoridazine
Risperidone
Fluphenazine
Thiothixene
Perphenazine
Chlorpromazine
Thioridazine
Haloperidol
Loxapine
Quetiapine
0 10 20 30 40 50 60
Risk of EEG Abnormalities (percent of subjects)
subjects, four loxapine-treated patients, and one given
molindone), to a maximum of 0.94 (SD=1.09) in 17 pa-
tients given clozapine monotherapy. Rates of EEG ab-
normalities of any type or severity associated with specific
treatments ranged from 13.3% in the untreated com-
parison subjects (or 0% among the few subjects given
quetiapine, loxapine, or molindone) to a high of 47.1% of
subjects given clozapine alone (Figure 1). Even in com-
bination with other antipsychotics, clozapine was asso-
ciated with a high risk of EEG abnormalities (39.1% of all
patients exposed to clozapine). Across all individual treat-
ment groups, as expected, risk of EEG abnormality was
strongly correlated with mean EEG scores (r=0.98, df=16,
p<0.0001).
Owing mainly to the strong impact of clozapine and
olanzapine, atypical antipsychotics generally, but incon-
sistently, carried significantly greater EEG abnormality
risk than typical neuroleptics (31.6% versus 14.5%). By or-
dinal logistic regression modeling, atypical antipsychotics
as a group were found to have significantly higher fre-
quencies of EEG abnormalities than typical neuroleptics
at each step of the four-level EEG abnormality rating
scores; EEG scores for atypical versus typical antipsychot-
ics averaged 0.63 (SD=0.99) versus 0.27 (SD=0.69), respec-
tively (z=3.35, p<0.001). The typical neuroleptics yielded
results similar to those seen in the antipsychotic-free sub-
jects for mean EEG scores (0.27 and 0.27) and risks of EEG
abnormalities (14.5% and 13.3%, respectively) (Table 1).
Among antipsychotics considered atypical, differences in
EEG abnormality risk among clozapine (47.1%), olanza-
pine (38.5%), and risperidone (28.0%) were not statisti-
cally significant (data not shown), and quetiapine (0%
risk) was used in only five cases (Table 1). Evidence of se-
vere EEG abnormality (spikes or spike-and-wave activity)
was found in eight of 293 patients (2.7%) at a nonsignifi-
cantly higher rate among those given an atypical antipsy-
chotic (5.1% [N=4 of 79] versus 1.9% [N=4 of 214] of those
112
given a typical antipsychotic) (p=0.22, Fishers exact test).
Antipsychotic drugs of low versus high potency did not
differ significantly in risk of EEG abnormalities (23.3% ver-
sus 17.7%, respectively; 2=2.43, df=1, p=0.12) nor in EEG
score (0.42 versus 0.34; z=0.30, p=0.76).
Few demographic, diagnostic, and treatment factors
were significantly associated with EEG abnormalities in
preliminary categorical comparisons based on binary EEG
status (normal versus abnormal). In descending order of
significance, the following were associated with EEG ab-
normalities: 1) use of clozapine or olanzapine versus all
other antipsychotics, 2) presence of hypertension (dias-
tolic pressure >90 mm Hg) versus no medical comorbidity,
3) atypical versus typical antipsychotics overall, 4) current
age >40 years (median age) versus younger, 5) diagnosis of
bipolar disorder versus all others, 6) longer exposure to
antipsychotic drug (i.e., >1.29 weeks), and 7) paradoxi-
cally, the absence versus presence of a comorbid DSM-IV
substance use disorder (Table 2). In addition, use of a ben-
zodiazepine tended toward an expected lower risk of EEG
abnormality (Table 2). There was no relationship between
daily dose and EEG abnormalities (e.g., for all antipsy-
chotic-treated patients, mean daily doses for those with
abnormal and normal EEG recordings were 3.51 mg/kg
[SD=2.27] and 3.82 mg/kg [SD=2.92], respectively; F=0.57,
df=1, 292, p=0.55).
We found no correlation between the presence or sever-
ity of EEG abnormalities and clinical outcome by the time
of hospital discharge. First, there was little difference in
likelihood of treatment response being rated (blind to EEG
status) as favorable between patients with (86.7%) and
without (80.3%) EEG abnormalities (2=1.31, df=1, p=0.25).
Length of hospital stay (adjusted for admission year) also
did not differ between patients with normal versus abnor-
mal EEG recordings (mean=27.6 days [SD=21.8] and 23.8
days [SD=17.7], respectively; F=0.81, df=1, 315, p=0.37).
Factors associated with EEG abnormalities in bivariate
comparisons (Table 2) were examined further by multi-
variate logistic regression modeling, which found that five
factors remained significantly associated with EEG ab-
normalities. In rank order of their odds ratios, these were
1) presence of hypertension, 2) use of an atypical antipsy-
chotic agent, 3) diagnosis of bipolar disorder, 4) age over
40, and 5) absence of cotreatment with a benzodiazepine
(Table 3). The overall multivariate regression model based
on these factors was strong (2=35.0, df=5, p<0.0001). The
risk factors, with the EEG-protective effects of benzodiaz-
epine cotreatment excluded, also showed cumulative ef-
fects leading to increasing probability of EEG abnormality:
2.9% (95% CI=0.06.2) with no risk factor present, 24.5%
(95% CI=17.231.7) with one factor, 34.2% (95% CI=16.6
48.3) with two, and 50.0% (95% CI=20.079.9) with three
considered. No subject had more than three of the five fac-
tors, and there were no significant interactions among the
factors.
Am J Psychiatry 159:1, January 2002
 CENTORRINO, PRICE, TUTTLE, ET AL.

TABLE 2. Factors Associated With EEG Abnormalities in 323 Hospitalized Psychiatric Patients

Abnormality Analysisb
Factor Risk (%) Odds Ratioa 95% CI 2 df z p
Specific drugs 11.2 2 <0.004
Clozapine or olanzapinec 43.3 4.97 1.3917.80 2.46 <0.02
Other 16.4 1.27 0.423.83 0.43 <0.67
None 13.3 1.00
Medical diagnosis 12.2 2 0.002
Hypertension 53.8 4.33 1.3713.70 3.37 0.002
Other 12.2 0.51 0.261.01 1.71 0.09
None 20.2 1.00
Type of antipsychoticd 10.2 2 0.001
Atypical 31.6 2.73 1.495.02 3.24 0.001
Typical 14.5 1.00
Current age 11.6 1 <0.001
>40 years 31.8 2.87 1.575.25 3.44 0.001
40 years 13.9 1.00
Bipolar diagnosis 4.8 1 0.03
Present 28.8 2.08 1.103.93 2.24 0.03
Absent 16.3 1.00
Weeks of antipsychotic treatmentd 5.2 1 0.03
>Median (1.29 weeks) 24.6 1.98 1.093.58 2.25 0.03
Median 14.2 1.00
Substance abusee 3.4 1 0.07
Present 12.8 0.53 0.261.08 1.75 0.08
Absent 21.7 1.00
Benzodiazepines 2.5 1 0.12
Present 16.2 0.62 0.351.12 1.58 0.12
Absent 23.7 1.00
a Comparator is listed last in each contrast.
b Chi-square is for overall regression model; z statistic tests significance of indicated regression coefficients.
c Risk associated with clozapine or olanzapine was also significantly different than that of other antipsychotics (2=18.0, df=1, p<0.0001).
d Comparison group was excluded.
e Patients with uncertain substance abuse status were excluded.

Discussion TABLE 3. Multivariate Logistic Regression Analysis of Predic-

tors of EEG Abnormalities in 323 Hospitalized Psychiatric
Patientsa
EEG abnormality rates and severity scores were evalu-
ated in 323 hospitalized psychiatric patients. Ratings were Odds
Predictor Ratio 95% CI z p
blind to treatment with a variety of antipsychotic agents as Hypertension 3.81 1.0513.80 2.04 0.05
well as a no-antipsychotic treatment condition. Specific Atypical antipsychotic 3.28 1.696.38 3.50 <0.001
antipsychotics varied widely in their association with EEG Bipolar diagnosis 2.88 1.425.87 2.92 0.003
Age >40 2.48 1.254.92 2.59 0.01
abnormalities. Among modern atypical agents, EEG ab- Benzodiazepine cotreatmentb 0.47 0.240.90 2.29 0.03
normality risk was highest with clozapine, followed by a Overall model: 2=37.0, df=5, p<0.0001.
olanzapine and risperidone, with the few quetiapine- b Protective factor.

treated patients having no abnormalities. Abnormality

rates among older neuroleptics ranged from 36.4% with
trifluoperazine to 7.3% with haloperidol, with intermedi-
ate rates in other neuroleptics of high or low potency
(13%14% with chlorpromazine, perphenazine, or thior-
idazine) and in untreated subjects. As there is no reason to
suspect that pretreatment EEG status differed systemati-
cally by drug, the marked differences encountered may be
largely drug specific. Contrary to expectation, chlorprom-
azine-equivalent dose (either in mg/day or mg/kg) did not
correlate with EEG abnormalities.
Clozapine has been especially strongly associated with
higher seizure risk, and EEG abnormalities are found in at
least one-third (12, 13, 1825) or more (12, 19, 20, 23) of
clozapine-treated patients and in 47.1% in the present
study. Seizure risk with clozapine probably increases with
drug dose and serum concentration (19, 24, 26). With
newer drugs, such studies are uncommon. Risperidone
has rarely been associated with severe EEG abnormalities
or overt epileptic seizures (27, 28). With olanzapine, risk of
EEG abnormalities (38.5%) was higher than expected from
its reported seizure risk (as low as 0.88% [29, 30]). We
found no EEG abnormalities in the five patients treated
with quetiapine, which has a low reported seizure risk
(0.75%) and only minor EEG effects (31).
Clinical factors significantly associated with EEG ab-
normalities included hypertension and older age. EEG ab-
normalities are uncommon in hypertension associated
with advancing age and without evidence of cerebrovas-
cular insufficiency or neurological damage (2). However,
advancing age can increase EEG variability, with some fo-
cal temporal slowing or slowing of average alpha EEG
frequencies (2, 17).
The observed protective association between benzodi-
azepine cotreatment and EEG abnormalities presumably

Am J Psychiatry 159:1, January 2002 113

EEG ABNORMALITIES AND ANTIPSYCHOTICS
reflects the anticonvulsant effect of these agents and their
tendency to suppress epileptiform activity and induce
EEG slowing (2, 3, 7). Slowing is also associated with phe-
nothiazines and butyrophenones as well as tricyclic anti-
depressants, monoamine oxidase inhibitors, lithium, an-
algesics, and some hallucinogens (2, 3, 32, 33). Low-
potency phenothiazines can induce generalized paroxys-
mal bursts in the EEG recording and, occasionally, epilep-
tic seizures (32). EEG abnormalities are found in nearly
two-thirds of patients treated with lithium, including
background slowing with high-voltage anterior delta ac-
tivity and a 17% risk of spike discharges (3, 33). Recent use
of lithium may contribute to the association found be-
tween EEG abnormalities and bipolar disorder.
A provocative hypothesis, based on limited data, is that
EEG abnormalities may be associated with clinical im-
provement in psychotic patients, either during treatment
(3436) or as a predictive factor before use of clozapine in
particular (37). However, we found no evidence of associa-
tion of EEG status and clinical improvement.
Limitations of this study include its retrospective de-
sign, with medical records and clinical EEG assessments
as the primary sources of data. There was no control over
when or why EEG recordings were obtained, knowledge of
pretreatment EEG status, nor control of treatments given,
and the numbers of subjects given some drugs were quite
small. The present clinical cohort also may be enriched
with patients with EEG abnormalities, although there is no
reason for such risk to be differentially associated with
specific treatments. Ratings of EEG abnormalities were
crude but were carried out blind to treatment and with
high test-retest reliability. The present study was unable to
specify the clinical significance of EEG abnormalities en-
countered. However, even ratings of 1 (mild) can be clini-
cally relevant: delirium can be associated with EEG slow-
ing and other mild changes (score of 1). Moderate
(score of 2) changes may suggest focal and structural le-
sions; severe changes (score of 3) may indicate seizure
disorder (3, 5, 1517). Nevertheless, prospective studies
are required to define the clinical significance of specific
types and levels of EEG abnormalities.
In conclusion, this preliminary study yielded several in-
teresting findings. 1) Some atypical antipsychotics carry a
higher average risk of EEG abnormalities than many typi-
cal neuroleptics. 2) This risk was greatest with clozapine
and unexpectedly high with olanzapine. 3) Risperidone
was similar to standard high-potency neuroleptics. 4) Que-
tiapine had a very low rate of EEG abnormality risk among
the very few subjects who received this agent. 5) Neither
drug potency nor daily or weight-corrected chlorprom-
azine-equivalent dose was associated with EEG abnormal-
ities. 6) Other risk factors significantly and independently
associated with EEG abnormalities included hypertension,
older age, and diagnosis of bipolar disorder, whereas
cotreatment with a benzodiazepine was a protective factor.
The present findings support the view that misattribution
114
of an EEG abnormality to an underlying brain disorder
rather than to a medication effect can confuse diagnosis
and complicate treatment. Finally, they encourage pro-
spective EEG analyses before and during treatment with
specific drugs and objective ratings of clinical changes.
Presented in part at the 153rd annual meeting of the American
Psychiatric Association, Chicago, May 1318, 2000. Received Jan. 24,
2001; revision received April 24, 2001; accepted June 26, 2001. From
the Bipolar and Psychotic Disorders Program, McLean Hospital. Ad-
dress reprint requests to Dr. Centorrino, Bipolar and Psychotic Disor-
ders Program, McLean Hospital, 115 Mill St., Belmont, MA 02478;
centorf@mcleanpo.mclean.org (e-mail).
Supported in part by a research award from Janssen Research
Foundation (Drs. Centorrino, Price, and Baldessarini), NIMH grant
MH-47370, a grant from the Bruce J. Anderson Foundation, and by
the McLean Private Donors Neuropharmacology Research Fund (Dr.
Baldessarini).
References
1. Berger H: ber das Elektrenkephalogram des Menschen. Arch
Psychiatr Nervenkr 1929; 87:527570
2. Fink M: EEG and behavior: association or disassociation in
man? Integrative Psychiatry 1993; 9:108123
3. Niedermeyer E, DaSilva F (eds): Electroencephalography: Basic
Principles, Clinical Applications, and Related Fields. Baltimore,
Williams & Wilkins, 1999
4. Stevens JR, Bigelow L, Denney D, Lipkin J, Livermore AH Jr,
Rauscher F, Wyatt RJ: Telemetered EEG-EOG during psychotic
behaviors of schizophrenia. Arch Gen Psychiatry 1979; 36:251
262
5. Bridgers SL: Epileptiform abnormalities discovered on electro-
encephalographic screening of psychiatric inpatients. Arch
Neurol 1987; 44:312316
6. Small JG, Milstein V, Malloy FW, Medlock CE, Klapper MH: Clini-
cal and quantitative EEG studies of mania. J Affect Disord 1999;
53:217224
7. Baldessarini RJ: Drugs and the treatment of psychiatric disor-
ders: depression and anxiety disorders, in Goodman and Gil-
mans The Pharmacological Basis of Therapeutics, 10th ed. Ed-
ited by Hardman JG, Limbird LE, Gilman AG. New York,
McGraw-Hill, 2001, pp 447483
8. Baldessarini RJ, Tarazi FI: Drugs and the treatment of psychiat-
ric disorders: psychosis and mania agents. Ibid, pp 485520
9. Roubicek J, Major I: EEG profile and behavioral changes after a
single dose of clozapine in normals and schizophrenics. Biol
Psychiatry 1977; 12:613633
10. Moore NC, Tucker KA, Brin FB, Merai P, Shillcut SD, Coburn KL:
Positive symptoms of schizophrenia: response to haloperidol
and remoxipride is associated with increased alpha EEG activ-
ity. Hum Psychopharmacol 1997; 12:7580
11. Itil TM, Soldatos C: Epileptogenic side effects of psychotic
drugs: practical recommendation. JAMA 1990; 147:10691071
12. Silvestri RC, Bromfield EB, Khoshbin S: Clozapine-induced sei-
zures and EEG abnormalities in ambulatory psychiatric pa-
tients. Ann Pharmacother 1998; 32:11471151
13. Devinsky O, Honigfeld G, Patin J: Clozapine-related seizures.
Neurology 1991; 41:369371
14. Baldessarini RJ, Katz B, Cotton P: Dissimilar dosing with high-
potency and low-potency neuroleptics. Am J Psychiatry 1984;
141:748752
15. American Electroencephalographic Society: Guidelines in EEG
and evoked potentials. J Clin Neurophysiol 1986; 3(suppl 1):1
152
Am J Psychiatry 159:1, January 2002

16. Santamaria J, Chiappa KH: The EEG in Drowsiness. New York,
Demos Press, 1987
17. Daly DD, Pedley TA (eds): Current Practice of Clinical Electroen-
cephalography. New York, Raven Press, 1990
18. Liukkonen J, Koponen HJ, Nousiainen U: Clinical picture and
long-term course of epileptic seizures that occur during cloza-
pine treatment. Psychiatry Res 1992; 44:107112
19. Gnther W, Baghai T, Naber D, Spatz R, Hippius H: EEG alter-
ations and seizures during treatment with clozapine: retro-
spective study of 283 patients. Pharmacopsychiatry 1993; 26:
6974
20. Haring C, Neudorfer C, Schwitzer J, Hummer M, Saria A, Hinter-
huber H, Fleischhacker WW: EEG alterations in patients treated
with clozapine in relation to plasma levels. Psychopharmacol-
ogy 1994; 114:97100
21. Malow BA, Reese KB, Sato S, Bogard PJ, Malhotra AK, Su TP,
Pickar D: Spectrum of EEG abnormalities during clozapine
treatment. Electroencephalogr Clin Neurophysiol 1994; 91:
205211
22. Welch J, Manschreck T, Redmond D: Clozapine-induced sei-
zures and EEG changes. J Neuropsychiatry Clin Neurosci 1994;
6:250256
23. Risby ED, Epstein CM, Jewart RD, Nguyen BV, Morgan WN, Risch
SC, Thrivikraman KV, Lewine RL: Clozapine-induced EEG abnor-
malities and clinical response to clozapine. J Neuropsychiatry
Clin Neurosci 1995; 7:466470
24. Freudenreich O, Weiner RD, McEvoy JP: Clozapine-induced
electroencephalogram changes as a function of clozapine se-
rum levels. Biol Psychiatry 1997; 42:132137
25. Baldessarini RJ, Frankenburg FR: Clozapine: a novel antipsy-
chotic agent. N Engl J Med 1991; 324:746754
26. Centorrino F, Baldessarini RJ, Kando J, Frankenburg FR, Volpi-
celli SA, Puopolo PR, Flood JG: Serum concentrations of cloza-
Am J Psychiatry 159:1, January 2002
CENTORRINO, PRICE, TUTTLE, ET AL.
pine and its major metabolites: effects of cotreatment with flu-
oxetine or valproate. Am J Psychiatry 1994; 151:123125
27. Umbricht D, Kane JM: Medical complications of new antipsy-
chotic drugs. Schizophr Bull 1996; 22:475483
28. Czobor P, Volavka J: Quantitative electroencephalogram exam-
ination of effects of risperidone in schizophrenic patients. J Clin
Psychopharmacol 1993; 13:332342
29. Beasley CM Jr, Tollefson GD, Tran PV: Safety of olanzapine. J Clin
Psychiatry 1997; 58(suppl 10):1317
30. Wyderski RJ, Starrett WG, Abou-Saif A: Fatal status epilepticus
associated with olanzapine therapy. Ann Pharmacother 1999;
33:787789
31. Wetzel H, Szegedi A, Hain C, Wiesner J, Schlegel S, Benkert O:
Seroquel (ICI-204-636), a putative atypical antipsychotic, in
schizophrenia with positive symptomatology: results of an
open clinical trial and changes of neuroendocrinological and
EEG parameters. Psychopharmacology (Berl) 1995; 119:231
238
32. Bente D, Itil T: Zur wirking des phenothiazinkorpes Megaphen
auf das menschliche hirnstrombild. Arzneim Forsch 1954; 4:
418423
33. Helmchen H, Kanowski S: EEG changes under lithium (Li) treat-
ment. Electroencephalogr Clin Neurophysiol 1971; 30:269
34. Koukkou M, Angst J, Zimmer D: Paroxysmal EEG activity and
psychopathology during treatment with clozapine. Pharmako-
psychiatr Neuropsychopharmakol 1979; 12:173183
35. Stevens JR: Clozapine: the yin and yang of seizure psychosis.
Biol Psychiatry 1995; 37:425426
36. Wilson WH: Do anticonvulsants hinder clozapine treatment?
Biol Psychiatry 1995; 37:132133
37. Pillay SS, Stoll AL, Weiss MK, Tohen M, Zarate CA Jr, Banov MD,
Cole JO: EEG abnormalities before clozapine therapy predict a
good clinical response to clozapine. Ann Clin Psychiatry 1996;
8:15
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