Article

Electroconvulsive Therapy Augmentation in

Clozapine-Resistant Schizophrenia: A Prospective,
Randomized Study
Georgios Petrides, M.D.
Chitra Malur, M.D.
Raphael J. Braga, M.D.
Samuel H. Bailine, M.D.
Nina R. Schooler, Ph.D.
Anil K. Malhotra, M.D.
John M. Kane, M.D.
Sohag Sanghani, M.D.
Terry E. Goldberg, Ph.D.
Majnu John, Ph.D.
Alan Mendelowitz, M.D.
Objective: Up to 70% of patients with
treatment-resistant schizophrenia do not
respond to clozapine. Pharmacological
augmentation to clozapine has been stud-
ied with unimpressive results. The authors
examined the use of ECT as an augmenta-
tion to clozapine for treatment-refractory
schizophrenia.
Method: In a randomized single-blind
8-week study, patients with clozapine-
resistant schizophrenia were assigned to
treatment as usual (clozapine group) or
a course of bilateral ECT plus clozapine
(ECT plus clozapine group). Nonrespond-
ers from the clozapine group received an
8-week open trial of ECT (crossover phase).
ECT was performed three times per week
for the first 4 weeks and twice weekly for
the last 4 weeks. Clozapine dosages re-
mained constant. Response was defined as
$40% reduction in symptoms based on
the psychotic symptom subscale of the
Brief Psychiatric Rating Scale, a Clinical
Global Impressions (CGI)-severity rating ,3,
and a CGI-improvement rating #2.
Results: The intent-to-treat sample included
39 participants (ECT plus clozapine group,
N=20; clozapine group, N=19). All 19 patients
from the clozapine group received ECT in the
crossover phase. Fifty percent of the ECT plus
clozapine patients met response criterion.
None of the patients in the clozapine group
met response criterion. In the crossover phase,
response was 47%. There were no discernible
differences between groups on global cogni-
tion. Two patients required the postponement
of an ECT session because of mild confusion.
Conclusions: The augmentation of cloza-
pine with ECT is a safe and effective
treatment option. Further research is re-
quired to determine the persistence of the
improvement and the potential need for
maintenance treatments.
Am J Psychiatry Petrides et al.; AiA:1–7

A s many as 30% of patients with schizophrenia respond

poorly to standard treatment with antipsychotic medi-
cations (1). Clozapine is the only medication shown to be
effective in antipsychotic-refractory patients (2, 3), but in
as many as 45% to 70% of these patients, symptoms are
also resistant to substantial improvement with clozapine
(2, 4). Limited options are available for individuals with
clozapine-resistant symptoms. Several augmentation strat-
egies have been evaluated, including addition of another
antipsychotic, mood stabilizers, anxiolytics, antidepressants,
and glutamatergic agents; however, no agent has shown
unequivocal efficacy in this population. Meta-analyses
of randomized placebo-controlled studies have found
little or no advantage of augmentation with antipsychotics
(5–8). The treatment of this subgroup of patients remains
an enormous challenge, with significant public health
implications.
Preliminary data from nonrandomized open-label studies
suggest that addition of ECT may be an effective alternative
for patients with clozapine-resistant symptoms. ECT, while
initially introduced for the treatment of schizophrenia in the
1930s, is currently most commonly used for the treatment
of depression. ECT and antipsychotics are considered to
exhibit synergistic effects (9). In 36 patients with symp-
toms resistant to typical antipsychotics, Kupchik et al. (10)
found that 67% of these patients benefitted from the com-
bination of clozapine and ECT, clozapine, or ECT alone.
In an open-label study in 11 clozapine nonresponders,
Kho et al. (11) found that the combination of clozapine
plus ECT to be efficacious. Havaki-Kontaxaki et al. (12)
reviewed all studies of clozapine-ECT combination in
schizophrenia or schizoaffective patients with strictly
defined clozapine-resistant symptoms, concluding that
preliminary evidence exists for the safety and short-term
efficacy of this combination. The main limitation of this
review was the small sample size (N=21) with data from one
open-label trial and six case studies. Finally, Masoudzadeh
and Khalilian (13) compared ECT, clozapine, and ECT-
clozapine combination in schizophrenia patients with
treatment resistant symptoms and noted a Positive and
Negative Syndrome Scale score reduction of 46% in the
clozapine group, 40% in the ECT group, and 71% in the
clozapine-ECT group. They concluded that the combina-
tion was significantly better than either treatment alone.
Therefore, our group initiated a pilot study of the effects
of adding ECT to clozapine. In an open-label prospective

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ECT AUGMENTATION IN CLOZAPINE-RESISTANT SCHIZOPHRENIA
study, we used bilateral ECT to treat 15 patients with schizo-
phrenia who had not responded to clozapine or partially
responded to clozapine, despite adequate doses for more
than 12 weeks. Nine of these patients (60%) met the a priori
response criterion of a 40% decrease in symptom ratings
as measured by the psychotic symptom subscale of the
Brief Psychiatric Rating Scale (BPRS) (14). Based on these
encouraging preliminary data, we have now conducted
the first prospective randomized study of the efficacy and
side-effect profile of ECT plus clozapine in schizophrenia
patients with clozapine-resistant symptoms.
Method
The study was conducted at The Zucker Hillside Hospital of
the North Shore-LIJ Health System. The study was approved by
the respective institutional review boards, and participants were
recruited from the inpatient units of the Zucker Hillside Hospital
at Glen Oaks, N.Y., and the Pilgrim State Psychiatric Center in
Long Island, N.Y.
Study Design and Procedures
In an 8-week random-assignment study incorporating nonblinded
treatment and blinded assessments, patients with antipsychotic-
and clozapine-resistant schizophrenia were assigned to two treat-
ment groups. One group received treatment as usual (clozapine
group) for 8 weeks, and the other received a course of bilateral
ECT in addition to their current pharmacotherapy regimen (ECT
plus clozapine). Nonresponders from the clozapine group received
an open 8-week trial of ECT (crossover trial) with the same
schedule and procedures as the randomized ECT plus clozapine
group.
Antipsychotic medication resistance was defined as a history
of at least two failed trials of 400 mg of chlorpromazine equiv-
alents for at least 4 weeks. Clozapine resistance was defined as
a history of persistence of psychotic symptoms after a trial of
clozapine of at least 12 weeks, at a blood level $350 ng/mL.
The inclusion criteria were diagnosis of schizophrenia ac-
cording to DSM-IV criteria; age 18–60 years; duration of illness
.2 years; resistance to at least two antipsychotics; clozapine
resistance; a baseline BPRS score of at least moderate (score of
4) on one of the four psychotic items (hallucinatory behavior,
suspiciousness, conceptual disorganization, and unusual thought
content) of the psychotic symptom subscale or a score of 12
on these four items combined; a Clinical Global Impressions
(CGI)-severity (15) rating of at least moderate (score of 4); capacity
to give informed consent; and for women of childbearing capacity,
a negative pregnancy test and patient agreement to use a medically
accepted form of contraception.
Exclusion criteria were schizoaffective disorder; bipolar dis-
order; current affective episode; ECT within 6 months; history of
epilepsy; severe neurological or systemic disorder that could sig-
nificantly affect cognition, behavior, or mental status (other than
tardive dyskinesia or neuroleptic-induced parkinsonism); psycho-
active substance dependence (other than nicotine or caffeine)
within 1 month prior to entering the study; a score .18 on the
24-item Hamilton Depression Rating Scale (HAM-D) (16); clin-
ical determination that mood stabilizers that could not be
discontinued were necessary; and pregnancy.
We also excluded patients with affective disorders and pro-
minent depressive symptoms because ECT is well known to be
effective in those situations, and we wanted to avoid contami-
nation of our results by improvement solely driven by the treat-
ment of the affective symptoms.
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The primary outcome measure was response rate. The re-
sponse criterion was defined a priori as improvement $40%
based on the psychotic symptom subscale, a CGI-severity rating
of mild or less (,3), and a CGI-improvement rating of much
improved (#2). For power calculations, we assumed a response
rate of 40% in the ECT plus clozapine group and 10% in the
clozapine group.
We chose to define response as a 40% reduction in symptoms
based on the psychotic symptom subscale, compared with the
traditional 20% in medication studies, recognizing that ECT adds
additional levels of complexity and requires increased effort by
both clinicians and patients.
Clozapine Group
Once randomly assigned, participants in both groups re-
mained on the clozapine dose at which they entered the study for
8 weeks. Concurrent use of other antipsychotic medications and
antidepressants was allowed as long as they were taken at a
stable dose for at least 12 weeks before entering the study.
Lorazepam, up to 6 mg per day, or diphenhydramine, up to
100 mg, were used as needed for anxiety, agitation, or insomnia.
ECT Plus Clozapine Group
ECT was performed with bilateral placement using the
Thymatron-DGx device (Somatics, Lake Bluff, Ill.). Seizure thresh-
old was determined at the first treatment. Dosing at subsequent
treatments was given at 50% above threshold. The seizure threshold
determination schedule and subsequent stimulus levels are shown
in Table 1. Medications used during anesthesia were glycopyrrolate
(0.1 mg–0.2 mg), methohexital (0.5 mg/kg–1 mg/kg), and succinyl-
choline (0.5 mg/kg–1 mg/kg). Participants signed a separate in-
formed consent for ECT, and standard institutional procedures for
ECT were followed.
ECT was administered three times per week for the first
4 weeks, then twice weekly for the next 4 weeks. If patients met
remission criteria before the completion of 8 weeks and showed
a plateau in their improvement for two consecutive ratings, ECT
was continued weekly through the end of 8 weeks.
Crossover ECT Trial
Participants from the clozapine group who did not respond to
8 weeks of continued pharmacotherapy received ECT augmen-
tation with the same schedule of treatments and ratings as the
ECT plus clozapine group for an additional 8 weeks.
Assessments and Raters
Eligible, consenting patients had a complete baseline medical
and psychiatric evaluation. DSM-IV diagnosis was established
using the Structured Clinical Interview for DSM-IV (17) by ex-
perienced raters. Patients were rated at baseline and weekly.
Final rating assessments were performed at the end of week 8,
except those from the cognitive battery, which was administered
at week 9 (i.e., 1 week after the last ECT session).
The raters were masked to the clinical assignment. Psychopa-
thology rating measures included the BPRS, CGI, HAM-D, the
Schedule for Assessment of Negative Symptoms (18), and the
Treatment Emergent Side Effects Scale (15), and rating assess-
ments were performed weekly.
To enhance objectivity, we videotaped the initial (baseline)
and final (week 8 or study exit) BPRS ratings. The tapes were
edited to remove any revealing statements about treatment, and
brief (2–5 seconds), nonessential portions from all tapes were
erased to create 3–10 skips in a random fashion, thus balancing
the presence of awkward skips that might be otherwise present
mostly in the ECT tapes. An independent, masked rater rated the
edited tapes. The average score between the two ratings at
baseline and the last visit was used for data analyses.
AJP in Advance

TABLE 1. ECT Dosing Algorithm
Seizure Threshold Dose at Subsequent
(% Energy) Treatment (% Energy)
5 10
10 15
20 30
40 60
60 90
A focused neuropsychological battery was performed at
baseline and at week 9. The battery was designed to assess
ECT-related effects, as well as measures of cognition relevant to
schizophrenia, and included the standard and modified Mini-
Mental State Examination (MMSE), the Rey Auditory Verbal
Learning Test, the paired-word and story-recall measures sub-
tests of the Randt Memory Battery, the letter-number span task,
the Trail-Making Test, the Controlled Oral Word Association
Test, the Competing Programs Test, and the Set Shifting Test.
Statistical Analysis
Histograms, q-q plots, and the Shapiro-Wilk test were used to
assess distribution of continuous variables. Based on the dis-
tribution, an independent-samples t test or Wilcoxon rank-sum
test was used to compare the baseline continuous variables be-
tween treatment groups. Chi-square test was used for categorical
variables. Since missing values may be dependent on the ob-
served outcomes, we assumed the missing data to be missing at
random, and hence analysis of the longitudinal data was con-
ducted utilizing a mixed-models approach. A random intercept
in the mixed-models was used to account for correlation of
measurements over time among the participants; the correla-
tional type was assumed to be unstructured. The difference in
slopes of the outcomes between the two treatment groups was
assessed using group-by-time interaction term in the mixed
models. Interrater reliability between the in-person and video
ratings was assessed using both consistency and absolute agree-
ment intraclass coefficients. The consistency intraclass coeffi-
cient between the ratings was 0.892 (95% confidence interval
[CI]=0.783–0.948; F=17.5, df=28, 28, p,0.0001). The absolute
agreement intraclass coefficient was 0.888 (95% CI=0.783–0.948;
F=17.5, df=28, 28, p,0.0001). All analyses were adjusted for age.
Results
Participants
Participant screening and enrollment flow data are pre-
sented in Figure 1 (92 were screened; 54 met inclusion
criteria; 13 refused participation; 41 signed consent). Thirty-
nine individuals were randomly assigned (ECT plus cloza-
pine group, N=20; clozapine group, N=19). The two groups
were well matched on demographic variables, including
sex, ethnicity, and psychopathology (Table 2). However,
the ECT-treated group was significantly younger than the
clozapine group; therefore, all analyses were adjusted for
age. Of the 20 participants assigned to ECT plus clozapine,
17 completed the 8-week trial, two dropped out early and
refused further ECT treatments, and one was removed from
the study because of persistence of involuntary movements.
In the clozapine group, 16 of the 19 patients completed the
8-week clozapine phase, and three patients dropped out
AJP in Advance
PETRIDES, MALUR, BRAGA, ET AL.
because they refused to continue to participate in the ratings
assessment while there was no change in their treatment.
However, all three of the patients who dropped out agreed
to participate in the crossover ECT phase, and all 19 par-
ticipants were included in that phase.
Clinical Efficacy Results
Ten of the 20 patients (50%) in the ECT augmentation
and none (0%) of the patients in the clozapine group met
the a priori response criterion. If the less conservative but
commonly used response criterion of a 20% reduction in
symptoms were used, we would have 12 (60%) responders.
Conversely, if an even stricter criterion were used, such as
a 50%, 60%, or 70% reduction in symptoms based on the
psychotic symptom subscale, we would have nine (45%),
six (30%), or three (15%) responders, respectively. None of
the clozapine patients would have responded with any of
the above criteria. Patients randomly assigned to ECT
augmentation were found to have significantly greater
reduction in ratings on the BPRS-psychosis subscale and
the CGI-severity scale compared with patients in the
clozapine group over time (Figure 2, Figure 3). Post hoc
analyses revealed that the ECT plus clozapine group had
significantly lower psychotic symptom subscale ratings by
week 3, and this significant difference persisted for the
remainder of the 8-week trial.
In the crossover phase, nine (47.4%) of 19 patients met the
response criterion. Overall, of the 39 patients who received
ECT in the randomized and crossover arms, 19 (48.7%) had at
least a 40% reduction in ratings on the psychotic symptom
subscale after 8 weeks of treatment.
Regarding negative symptoms, there were no significant
differences between the two groups and in group-by-time
interactions in analyses with the Scale for the Assessment
of Negative Symptoms on global measures for affective
flattening (F=0.98, df=1, 39.3, p=0.33), alogia (F=0.03, df=1,
40.1, p=0.87), avolition-apathy, (F=0.76, df=1, 39.3, p=0.39),
and anhedonia-asociality (F=1.87, df=1, 39.7, p=0.18). The
above analysis was based on actual differences from
baseline to final visit. A sensitivity analysis based on per-
cent change scores in the above measures also showed no
statistically significant differences between the groups (see
table in the online data supplement).
Side Effects
One patient in the ECT plus clozapine group was re-
moved from the study because of recurrence of preexisting
involuntary “jerky” movements that raised clinical con-
cerns of seizure activity. These concerns were not sub-
stantiated by electroencephalographic studies.
There were no side-effect differences between the
two groups in any rated symptom, and there were no
treatment-related side effects, except for two occasions
when patients in the ECT plus clozapine group were rated
as mildly confused and treatment was postponed until the
next day.
ajp.psychiatryonline.org 3
ECT AUGMENTATION IN CLOZAPINE-RESISTANT SCHIZOPHRENIA
FIGURE 1. CONSORT Diagram for Patients With Clozapine-Resistant Schizophrenia
Randomly assigned (N=39)
ECT (N=20, 51%)
Completers (N=17)
Early termination (N=3)
Responders Nonresponders
(N=10, 50%) (N=10, 50%)
We did not observe any peculiarities in EEG or motor
seizure expression, or any prolonged seizures, during ECT.
There were no spontaneous seizures among any of the
study patients.
Cognitive Effects
Because of potential concerns about the cognitive side
effects of ECT, we included an extensive neurocognitive
battery. We assessed multiple cognitive domains, includ-
ing global mental state, speed of processing, executive
function, and episodic memory. The two treatment groups
were well matched on each of the neurocognitive variables
at baseline, including a global measure of cognitive func-
tion (using MMSE).
Neither group demonstrated a significant change in
the global neurocognitive measures tested from baseline
to endpoint. The mean MMSE scores for the ECT plus
clozapine group were 22.6 (SD=1.2) at baseline and 23.1
(SD=1.2) at week 9, and mean scores for the clozapine
group were 22.2 (SD=1.0) and 23.4 (SD=1.2), respectively.
Speed measures generally demonstrated significant
group-by-time interactions such that the clozapine group
4 ajp.psychiatryonline.org
Screened (N=92)
Met screening criteria (N=54, 59%)
Signed informed consent (N=41)
Refused study procedures (N=2)
No ECT (N=19, 49%)
Completers (N=16)
Early termination (N=3)
Responders Nonresponders
(N=0, 0%) (N=19, 100%)
ECT: nonrandomized
(N=19)
Responders Nonresponders
(N=9, 47%) (N=10, 53%)
improved slightly and the ECT plus clozapine group de-
clined. For tests of visual and verbal memory, significant
interaction effects were less consistently found. For exec-
utive function (Trail-Making Test, Part B, letter-number
span task) interaction effects were not found. Results
are presented in the second table of the online data
supplement.
In general, our cognitive findings indicate that speed of
processing was sensitive to the effects of ECT administra-
tion when measured at a subacute time point (i.e., within 1
week of the final 8-week ECT course). Results in the do-
mains involving executive function and episodic memory
were less consistently found. Clinically, the degree of
cognitive burden shortly after the trial was felt to be
consistent with the clinical experience with ECT.
Clozapine Dosage and Plasma Levels
The mean clozapine dosage for the ECT treatment
group at baseline was 525.0 mg/day (SD=224.3), and the
mean dosage for the clozapine group was 511.1 mg/day
(SD=171.0). There were no significant differences between
groups. The clozapine daily doses remained unchanged
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 PETRIDES, MALUR, BRAGA, ET AL.

TABLE 2. Demographic and Clinical Characteristics of Patients With Clozapine-Resistant Schizophrenia

Variable ECT Plus Clozapine Group (N=20) Clozapine Group (N=19)
N % N %
Sex
Male 15 75 13 68.4
Female 5 25 6 31.6
Race/ethnicity
Caucasian 11 55 10 52.6
African American 5 25 6 31.6
Hispanic 2 10 3 15.8
Other 2 10 0 0
Mean SD Mean SD
Age (years)a 35.70 2.27 42.78 1.82
Brief Psychiatric Rating Scale (BPRS) total score 45.68 1.87 46.42 2.55
BPRS psychotic symptom subscale score 16.58 0.86 16.89 0.9
Clinical Global Impressions-severity score 5.35 0.02 5.53 0.22
Hamilton Depression Rating Scale score 14.90 1.64 16.79 1.58
Mini-Mental State Examination (MMSE) score 22.60 1.2 22.2 1.0
Modified MMSE score 44.78 1.89 39.76 39.76
Clozapine level (ng/mL) 854.8 278.1 828.9 267.5
a
The p value was calculated using Wilcoxon rank-sum test (p=0.03; W=269).

for each patient throughout the course of the study. There
were no significant differences between groups in mean
plasma levels (clozapine plus norclozapine) at baseline
and at endpoint.
ECT
The average number of ECT treatments in the random-
ized phase was 15.8 (SD=4.2), and the average number of
treatments in the crossover phase was 14.3 (SD=5.3).
The stimulus dose expressed as “percent of energy” on
the Thymatron device is presented in Table 1. The average
stimulus levels at the beginning of the course and at the
final ECT session are similar to those observed in clinical
practice in patients not receiving clozapine.
Discussion
To our knowledge, this is the first prospective random-
ized controlled study with masked raters assessing the
efficacy of ECT as an augmentation strategy for patients
with schizophrenia resistant to or partially responsive to
clozapine. The results of this study suggest that ECT is
a safe and effective treatment option for these patients and
confirm findings from smaller uncontrolled studies and
from earlier case reports (11, 12). The response rates of
50% observed in the randomized arm and 47% in the
crossover arm compare favorably to all other suggested
augmentation strategies for clozapine in this population.
The fact that none of the patients in the clozapine group
met the response criteria was not unexpected because our
selection criteria required a period of at least 8 weeks of
clozapine treatment at a steady dose without clinical
improvement. The lack of effects with regard to negative
symptoms precludes the attribution of response to the
improvement of negative symptoms that may often be
misinterpreted as depressive symptoms and vice versa.
ECT is the oldest biological treatment used in modern
psychiatry. It was introduced as a treatment for schizo-
phrenia in the 1930s, at a time when no medications were
available. With the introduction and widespread use of
antipsychotic medications in the 1950s, its use in schizo-
phrenia dramatically declined. Yet, there are certain con-
ditions in the course of the illness when rapid results are
required, such as cases with prominent catatonic symp-
toms, suicidality, and agitation or in cases of neuroleptic
malignant syndrome (19). In these cases, ECT is used with
very good results. In our study, we demonstrated that ECT
also may be useful in patients with chronic schizophrenia
with positive symptoms not adequately responsive to anti-
psychotic medications, including the last resort of phar-
macotherapy, clozapine.
There are several aspects of our study and its design that
are worth mentioning. We paid particular attention to
patient selection in an effort to study the effects of ECT on
purely schizophrenia patients. We excluded patients with
prominent affective symptoms to avoid contamination of
our data by improvements driven solely or partially by the
treatment of these symptoms that respond to ECT. In
order to maintain the blind in a study comparing treat-
ments that are so obviously different, we implemented
strict procedures, including videotaping of baseline and
exit interviews and independent “off-line” ratings. We in-
cluded a crossover arm to strengthen the results observed
in the randomized phase. Perhaps the most significant
element of the study design was our a priori response
criterion. We defined response as a 40% reduction in
symptoms based on the psychotic symptom subscale, a
level twice as high as the traditional 20% used in most
medication-resistant schizophrenia trials. This is in rec-
ognition of the fact that the administration of ECT adds
additional levels of complexity and risk to the treatment of

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ECT AUGMENTATION IN CLOZAPINE-RESISTANT SCHIZOPHRENIA

FIGURE 2. Changes in Brief Psychiatric Rating Scale (BPRS) response criteria. These are among the highest response
Psychosis Subscale Results Over Timea rates ever recorded in this patient population.
20 There were several theoretical concerns regarding the
concurrent use of ECT and clozapine, most notably the
possibility of prolonged or spontaneous seizures. In our
sample, we did not observe any such occurrences. On
BPRS Total Psychosis

15 the contrary, there were instances that required us to

administer stimuli at 100% of the device capacity in order
to elicit an adequate seizure. This over-time increased
resistance to seizure induction is in line with clinical
10 experience and reflects the fact that ECT has known
antiepileptic properties causing the seizure threshold to
increase over the course of ECT treatment.
With regard to the cognitive effects of the combined
treatment, we did not observe any unusual effects of ECT.
0 2 4 6 8
Our patients were severely ill, and their cognitive perfor-
Weeks
mance was, as expected, relatively low, with an average
a
The graph shows the changes in psychosis symptoms in the baseline MMSE score of 22. The fact that there was no
clozapine group (blue line; phase 1) and the ECT plus clozapine additional impairment after the course of ECT may reflect
group (red line; phase 1). Treatment-by-time interaction: F=5.38,
df=8, 238, p,0.0001. The degrees of freedom for mixed-models the fact that some aspects of cognitive function improved
analysis were obtained using Satterthwaite’s method. Error bars as a result of decreased disorganization, thus counter-
represent standard deviations. acting the expected transient memory impairment often
seen with ECT.
There are limitations of the study that need to be ad-
FIGURE 3. Changes in Clinical Global Impressions (CGI)-
dressed. First, there was no placebo arm, since sham ECT
Severity Scale Ratings Over Timea
studies are not considered ethical. Second, the number of
8
patients was relatively low, and our sample included only
inpatients. However, this is the largest study of this nature,
7
and the comparative effects between the two groups are
very strong. Third, there was an age difference between the
two groups, with the clozapine group being older. One
might assume that this may make symptoms in this group
CGI Severity

6
more resistant to treatment. Nevertheless, all group dif-
ferences remained significant after correcting for age,
5 and, more importantly, the older clozapine group had an
equally strong response to ECT in the crossover phase.
Finally, the duration of the study was relatively short and
4 did not allow for conclusions regarding the long-term
effects of ECT in this population. As in the case of the
treatment of depression with ECT, it is likely that mainte-
3
0 2 4 6 8 nance treatment is required for those patients who respond
Weeks to ECT plus clozapine, but this should be the focus of
a further research.
The graph shows the changes in symptom severity in the clozapine
group (blue line; phase 1) and the ECT plus clozapine group (red
line; phase 1). Treatment-by-time interaction: F=5.00, df=8, 238,
p,0.0001. The degrees of freedom for mixed-models analysis were Conclusions
obtained using Satterthwaite’s method. Error bars represent
standard deviations. The augmentation of clozapine with ECT for the treat-
ment of clozapine-resistant schizophrenia is a safe and
effective treatment option. In this severely ill group of
schizophrenia, requires increased effort by both clinicians patients with treatment-resistant symptoms, for whom
and patients, and therefore should be met with increased there are few clinical alternatives, we demonstrated a 50%
expectations. response rate using a conservative 40% reduction in
The finding that must be emphasized here is that in this symptoms criterion, and 60% response rate using conven-
group of patients with severe treatment-resistant symp- tional response criteria. To our knowledge, these are the
toms, 50% responded with the demanding 40% reduction in highest response rates reported with any type of clozapine
symptoms criterion, and 60% responded with conventional augmentation. Further research is required to determine

6 ajp.psychiatryonline.org AJP in Advance


the persistence of the results and the need for mainte-
nance treatments.
Received June 17, 2013; revisions received Feb. 25 and May 5,
2014; accepted June 6, 2014 (doi: 10.1176/appi.ajp.2014.13060787).
From the Division of Psychiatry Research, The Zucker Hillside
Hospital, North Shore-LIJ Health System, Glen Oaks, N.Y., and The
Feinstein Institute for Medical Research, Manhasset, N.Y. Address
correspondence to Dr. Petrides (Petrides@lij.edu).
Dr. Petrides has received research support from Amgen, Astra
Zeneca, Corcept, Eli Lilly, NIMH, Proteus, St. Jude Medical, and
Sunovion, and he has served on an advisory panel for Corcept. Dr.
Schooler has received honorarium from Lundbeck, advisory board
honoraria from Amgen, Eli Lilly, EnVivo, Janssen Psychiatry, Roche,
and Sunovion, and research grant support from Genentech, Neuro-
crine, and Otsuka. Dr. Malhotra has served as a consultant to
Genomind. Dr. Kane has served as a consultant to or on the advisory
board or speaker’s bureau of Alkermes, Bristol-Myers Squibb, Eli Lilly,
Forest, FORUM, Genentech, H. Lundbeck, Intracellular Therapeutics,
Janssen, Johnson and Johnson, Otsuka, Reviva, and Roche, and he is
a shareholder with MedAvante. All other authors report no financial
relationships with commercial interests.
Supported by an RO1 grant from NIMH to Dr. Petrides (MH-603930).
The authors thank Dr. Max Fink for his contribution to the con-
ceptualization of the study, mentorship, support, and tireless enthu-
siasm for this line of research.
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