ECT article

1. Electroconvulsive Therapy Augmentation in
Clozapine-Resistant Schizophrenia: A
Prospective, Randomized Study
Georgios Petrides, Chitra Malur, Raphael Braga, Samuel Bailine, Nina Schooler, Anil
Malhotra, John Kane, Sohag Sanghani, Terry Goldberg, Majnu John, Alan Mendelowitz
Am J Psychiatry. 2014 Aug 26. doi: 10.1176/appi.ajp.2014.13060787. [Epub ahead of
print]

2. American Journal of Psychiatry
• Editor: Robert Freedman, M.D
• Published every month
• Impact factor of 14.721 (Journal Citation reports,
2012)
• Ranking is third among 135 journals in the
category "Psychiatry“ according to “scimago
journal report 2013

3. DEFINING TREATMENT RESISTANT
SCHIZOPHRENIA
• Kane’s criteria, 1988
• 1. treatment with different classes of anti-psychotics at equal doses of
1000mg/day of chlorpromazine for at least 3 periods of 6 weeks in the last 5 years
without significant clinical improvement
• 2. reduction of at least 20% on the BPRS scale, score>35 points on the BPRS scale
after treatment, CGI score>3 after treatment with 60mg/day of haloperidol for 6
weeks
• 3. BPRS score >45, score >2 on BPRS items of conceptual disorganizaton, unusual
thoughts, hallucinatory behaviour and mistrust, CGI >4

4. • Kane’s modified criteria. ( Fabre et al, 1992, Kane et al 1993, Barnes et al,
1996)
• 1. treatment with different classes of anti-psychotics at equal doses of
400-600 mg/day of chlorpromazine for at least 2 periods of 6 weeks in the
last 5 years without significant clinical improvement
• 2. reduction of at least 20% on the BPRS scale, score>35 points on the
BPRS scale after treatment, CGI score>3 after treatment with 60mg/day of
haloperidol for 6 weeks
• 3. BPRS score >45, score >2 on BPRS items of conceptual disorganizaton,
unusual thoughts, hallucinatory behaviour and mistrust, CGI >4
•

5. Introduction
• 30% of schizophrenics respond poorly to standard anti-
psychotic treatment.
• Clozapine is the only medication shown to be effective
• But in 45-70% of these patients, even Clozapine is shown to
be resistant

6. Available options for Clozapine
resistant Patients
• Meta analysis of Randomized placebo controlled studies has
not been clearly able to show any substantial benefit of
augmentation with anti- psychotics

7. ECT as an augmentation strategy
Kupchik et al, 2000 in their meta analysis found that 67% of these
treatment resistant patients benefitted with combination of
Clozapine and ECT
Kho et al, 2004 found combination of Clozapine plus ECT to be
efficacious but had only 11 resistant patients.
Havaki-Kontaxaki et al, 2006 in a review article concluded that
preliminary evidence exists for safety and short term efficiacy of
this combination.
Masoudzadeh and Khalilian, 2007 comparing groups of these resistant
patients on Clozaoine alone, ECT alone and Combination of
Clozapine and ECT found that the combination group fared
significantly better.

8. Aims and Objectives
• To study ECT as an effective augmentation strategy for
Clozapine resistant patients with Schizophrenia

9. METHOD
• Place of study- Zucker Hillside hospital of the north shore – LJI
health system.
• Only inpatients from the hospital were included in the study.
• Duration of study- 8 weeks of treatment trial followed by 8
weeks of cross over trial.
Study Design
• Randomized controlled trial with non blinded treatment and
blinded assessments with a crossover trial for non responders

10. Definitions used for resistance
• Anti psychotic resistance – history of at least 2 failed trials of
400 mg of chlorpromazine equivalents for at least 4 weeks.
• Clozapine resistance- history of persistence of psychotic
symptoms after a trial of Clozapine of at least 12 weeks, at a
blood level of >= 350ng per ml

11. Inclusion Criteria
• Diagnosis of Schizophrenia, DSM IV criteria
• Age 18-60 years
• Duration of illness> 2 years
• Resistance of at least 2 anti psychotics(as per above the definition)
• Clozapine resistance(as per the definition)
• A baseline BPRS score of atleast 4 on one of the 4 psychotic items on the
psychotic symptom subscale or a score of 12 on these 4 items combined
• A CGIS rating of at least 4
• Capacity to give informed consent
• For women of child bearing age, a negative pregnancy test and patient
agreement to use a medically accepted form of contraception

12. Exclusion criteria
• Schizoaffective disorder
• Bipolar disorder
• Current affective episode
• ECT within 6 months
• History of epilepsy
• Severe neurological or systemic disorder that could significantly affect
cognition, behaviour or mental status
• Psychoactive substance dependence(other than caffeine or nicotine)
within 1 month prior to entering the study
• A score >18 on the 24 item Hamilton Depression rating scale
• Clinical determination that mood stabilizers that could not be
discontinued were necessary

13. Primary outcome
• Response criterion- improvement >= 40% based on the
psychotic symptom subscale
• A CGI Severity rating of 3 or less
• A CGI Improvement rating of much improved (<=2)

14. Method of study
• Participants were randomly assigned into 2 groups – those
who were to receive Clozapine alone and those who were to
receive Clozapine and ECT
Clozapine Group
• Concurrent use of other antipsychotics allowed if taken at a
stable dose of least 12 weeks before study began.

15. ECT and Clozapine group
• ECT was performed by bilateral placement.
• ECT was administered 3 times per week for the first 4 weeks
and then twice weekly for the next 4 weeks
• Clozapine was continued at the same doses as before the
study began
• Crossover trial
• Participants from the Clozapine group who did not respond to
8 weeks of continued pharmacotherapy received ECT
augmentation with the same schedule of treatment and
ratings as the ECT plus Clozapine group for an additional 8
weeks

16. Assessments and raters
• DSM-IV diagnosis was established using the Structured Clinical
Interview for DSM-IV
• Patients were rated at baseline and weekly.
• The raters were masked to the clinical assignment.
• Scales used-
• BPRS, CGI, HAM-D, the Schedule for Assessment of Negative
Symptoms, and the Treatment Emergent Side Effects Scale
• A focused neuropsychological battery was performed at
baseline and at week 9 to study the cognitive adverse effects
of ECT

17. Statistical analyses
• Histograms, q-q plots and shapiro wilk test – to assess
distribution of continuous variables
• For comparison of data Independent-samples t-test and
Wilcoxon rank sum test was used for continuous variables
Chi square test for categorical variables
Analysis of the longitudinal data was done using the mixed
models approach

18. • consistency intraclass coefficient between rating- 0.892
• Absolute agreement intraclass coefficient- 0.888
• All analyses were adjusted for age

19. Results
Of the 20 participants assigned to ECT plus clozapine, 17
completed the 8-week trial,
In the clozapine group, 16 of the 19 patients completed the 8-
week clozapine phase but all participated in the crossover
phase
Ten of the 20 patients (50%) in the ECT augmentation and none
(0%) of the patients in the clozapine group met the response
criterion defined

20. • 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.

21. Changes in BPRS psychotic subscales and CGI severity rating scales over
time
(red line- ECT plus Clozapine and blue line- ECT alone)

22. • In the crossover phase, 9 of the 19 patients (47.4%) met the
response criteria
Cognitive effects
• Neither group demonstrated a significant change in the global
neurocognitive measures tested from baseline to endpoint.

23. Clozapine dosages 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.

24. Discussion
• 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.
• 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
• With regard to the cognitive effects of the combined
treatment, there were no unusual effects of ECT

25. Limitations
• No placebo arm( sham ECT not acceptable)
• Small sample size that included only inpatients
• Age difference between the 2 groups
• Duration of the study was short so long term effects could not
be elicited.
• In the statistical analyses of data, only baseline and final
scores were used.
• A treatment group receiving ECT alone was not included in
the study.

26. Conclusions
• The augmentation of clozapine with ECT for the treatment of
clozapine-resistant schizophrenia is a safe and effective
treatment option.
• Further research is required to determine the persistence of
results and the need for maintenance treatment.

27. Study information
• Some authors have received research support from
pharmaceutical companies
• All authors report no financial relationships with commercial
interests
Supported by an RO1 grant from NIMH to Dr. Petrides