Psychiatry Research 249 (2017) 349353

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Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Eectiveness of electroconvulsive therapy in patients with treatment MARK

resistant schizophrenia: A retrospective study

Sandeep Grover , Subho Chakrabarti, Nandita Hazari, Ajit Avasthi
Department of Psychiatry, Post-Graduate Institute of Medical Education and Research, Chandigarh 160012, India

A R T I C L E I N F O A BS T RAC T

Keywords: This study aimed to evaluate the eectiveness of electroconvulsive therapy (ECT) among patients with treatment
Clozapine resistant schizophrenia (TRS). Records of patients who had received ECT were reviewed to identify patients with
Electroconvulsive therapy TRS who were administered ECT in combination with clozapine. Socio-demographic, clinical data and ECT
Treatment-resistant details were extracted. The most common diagnosis was of paranoid schizophrenia (49%) followed by
Clozapine non-response
undierentiated schizophrenia (36%). A-fth (22%) of the patients were judged to have poor response to
Schizophrenia
clozapine. The mean number of ECTs given were 13.97 (SD-7.67) and mean clozapine dose was 287.5 mgs/day
(SD-100.1). About two-thirds (63%) of the patients showed > 30% reduction in scores on dierent symptom-
rating scales with combined use of clozapine and ECT. Among clozapine non-responders, approximately 69%
responded to the combination. Post-ECT rise in blood pressure was the most common side eect (16.9%)
followed by prolonged seizures (7%). Long-term follow-up data was available for 47 out of the 59 patients. More
than two-third (N=34; 72%) followed-up for an average of 30 months (SD 32.3; range: 1120), maintained well
with continued clozapine treatment. To conclude, results of this study further endorse the eectiveness, safety
and long-term benets of the clozapine-ECT combination in TRS and clozapine-refractory schizophrenia.

1. Introduction (Chanpattana and Andrade, 2006). Moreover, several reviews which

Antipsychotics are the main stay of treatment of schizophrenia.
However, 2033% of patients with schizophrenia do not respond to
conventional antipsychotics. Those who do not respond to two or more
adequate trials of antipsychotics are considered to have treatment
resistant schizophrenia (TRS) (Kane et al., 1988). The management of
patients with TRS is demanding because of the requirement for more
intensive treatment and the poor prognosis that characterizes the
condition. Though clozapine is the only medication of proven value
in TRS, 3070% of such patients respond poorly to this medication as
well (Chakos et al., 2001; Lieberman et al., 1994; Meltzer et al., 1990).
Various augmentation strategies have been tried in patients with
clozapine-resistance, including medications, electroconvulsive therapy
(ECT), and psychosocial treatments.
Electroconvulsive treatment has been used for the management of
schizophrenia ever since the treatment was rst introduced. However,
over the years the use of ECT in patients with schizophrenia has
declined in developed countries, and its use is mostly restricted to those
who are refractory to pharmacotherapy (Chanpattana and Andrade,
2006). In contrast, in resource constrained, low-income countries, ECT
is used quite frequently for management of schizophrenia
have evaluated the role of ECT in schizophrenia suggest that ECT when
used in combination with antipsychotics may be more eective than
either treatment, particularly in those with poor response to antipsy-
chotics (Painuly and Chakrabarti, 2006; Tharyan and Adams, 2005;
Chanpattana and Andrade, 2006; Gazdag and Ungvari, 2011; Zervas
et al., 2012; Pompili et al., 2013).
Studies evaluating the use of ECT among patients with TRS have
been conducted either among patients on non-clozapine antipsycho-
tics, or among those on clozapine, usually poor responders to clozapine.
Preliminary evidence for the ECT augmenting the response to rst-
generation antipsychotics in TRS (Havaki-Kontaxaki et al., 2006) was
conrmed by a series of open trials from Thailand, which examined the
ecacy of combined bilateral ECT and upenthixol in patients with
TRS (Chanpattana et al., 1999a, 1999b; Chanpattana, 2000;
Chanpattana and Andrade, 2006), and found that more than half of
those with TRS responded to the combination. Continuation ECT along
with upenthixol was more eective in relapse prevention than either
treatment used alone among those patients with TRS who respond to
the combined treatment during the acute phase (Chanpattana et al.,
1999b). Response to ECT was mainly predicted by shorter duration of
current episode and less severe negative symptoms at baseline

Corresponding author.
E-mail address: drsandeepg2002@yahoo.com (S. Grover).

http://dx.doi.org/10.1016/j.psychres.2017.01.042
Received 16 April 2016; Received in revised form 5 November 2016; Accepted 17 January 2017
Available online 18 January 2017
0165-1781/ 2017 Elsevier B.V. All rights reserved.

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S. Grover et al.
(Chanpattana and Andrade, 2006). Other open trials have also found
similar response rates with combinations of unilateral or bilateral ECT
with several second-generation antipsychotics, other than clozapine
(Tang and Ungvari, 2002, 2003; Ravani et al., 2009).
Studies on combined use of clozapine and ECT in TRS started in the
form of case reports or case series involving few patients. Two regimens
were commonly employed while using the clozapine-ECT combination
in these studies- either ECT was used following a trial of clozapine, in
patients who have responded poorly to the drug, or the two have been
administered together. Despite the limited nature of the evidence, the
safety and short-term ecacy of concurrent administration of cloza-
pine and ECT in clozapine non-responders was amply demonstrated
(Kupchik et al., 2000; Kho et al., 2004; Havaki-Kontaxaki et al., 2006;
Braga and Petrides, 2005; Tranulis et al., 2006). Subsequently, several
other open or single-blind cross-over randomised controlled trials have
endorsed the ecacy of the clozapine-ECT combination in patients
with TRS, who respond poorly to clozapine (Masoudzadeh and
Khalilian, 2007; Koen et al., 2008; Flamarique et al., 2012). In a
previous study, we also found benecial eect of use of clozapine and
ECT combination (Grover et al., 2015a). More recently, in a rando-
mized single-blind 8-week study of patients with clozapine-resistant
schizophrenia, 50% of patients on clozapine-ECT combinations re-
sponded to the treatment (Petrides et al., 2015). Moreover, when
patients treated with clozapine alone were subsequently treated with
the ECT-clozapine combination, response rates of 47% were obtained
in this cross-over phase. A recent systematic review and metanalysis
included data of 71 patients with TRS. The data was extracted from 4
open label trials (N=32) and one randomized controlled trial (N=39)
and the authors reported response rate of ECT-clozapine combination
to be 54%. When the authors included data from retrospective studies,
case reports and case series, information was available for 192 patients.
Response rate with combination of ECT-clozapine was 66% with mean
number of ECT being used were 11.3. Of the 84 patients who
responded to the combination, follow-up data was available for 62
patients. Of these 62 patients, about one-third (32%) relapsed follow-
ing stoppage of ECT (Lally et al., 2016).
This brief review suggests that the literature on the use of clozapine-
ECT combination in TRS is scarce, and there is ample scope for further
investigation. Accordingly, the primary aim of this retrospective study
was to evaluate the usefulness of the clozapine- ECT combination
among patients with TRS. The secondary aims were: 1) to evaluate the
ECT related side-eects in patients receiving clozapine; and 3) to
explore the long-term outcome of patients who had received clozapine
and ECT.
2. Methodology
2.1. Ethical clearance
The study was conducted in the department of psychiatry of a
multi-specialty tertiary-care hospital in north-India. The study fol-
lowed a retrospective design and was approved by the Institute Ethics
Committee.
2.2. Setting
ECT is administered to both outpatients and inpatients in this
department. ECT is more commonly used among patients with
psychosis; the usual indications are catatonia, severe agitation or
aggression, suicidality, and antipsychotic refractory symptoms. The
decision to start ECT is made by the consultant-in-charge and his/her
team after detailed assessment and review of past treatments. In
complicated cases, a second opinion is usually sought from other
consultants. Once the treating-team decides that ECT is clinically
indicated, written informed consent is sought from both patients and
their relatives, after a detailed explanation of the process. ECT is
350
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Psychiatry Research 249 (2017) 349353
administered only on a voluntary basis. Consenting patients undergo
physical assessment and investigations as required, and are also
assessed by the anaesthetist. If found t, the patient is administered
brief-pulse, bilateral, modied ECT, two to three times a week, with
proper monitoring of vital status, seizure parameters, and of the post-
ECT period. An indigenously manufactured brief-pulse, constant-
energy machine is used. Atropine or glycopyrrolate are used as
premedications, thiopentone is used for induction and succinylcholine
is used for muscle relaxation. Stimulus parameters include charge
ranging from 60 to 456 milli-coulombs and stimulus duration ranging
from 0.5 to 3.8 s. The cu method is used to estimate seizure duration.
Motoric seizure of at least 15 s is regarded an eective treatment. EEG
monitoring is not done routinely. ECT is discontinued if the clinical
response reaches a plateau over two consecutive ECT treatments, if
there is remission of target symptoms, or if patient develops complica-
tions during ECT, which contradict further use. ECT is administered by
trainee psychiatrists supervised by fully-qualied residents and con-
sultants. Details of the treatment are documented in the patient's case
notes and in a computerized ECT-register, by the doctor administering
ECT. Clozapine is generally used in patients who do not respond to two
or more adequate antipsychotic trials.
Patients are considered to have TRS, if they fail to respond to two or
more adequate antipsychotic trials. For operationalization, a failed trial
is dened as non-response/minimal response (dened as less than 20%
clinical improvement) with an antipsychotic given for a period of 6
weeks in the therapeutic doses with good medication compliance (i.e.,
more than 75% intake of the prescribed doses). Clozapine resistance is
dened as failure of a 12 weeks trial of clozapine, i.e., minimal response
(dened as less than 20% clinical improvement) or partial response
(response less than 25% clinical improvement) to clozapine given in the
therapeutic doses with good medication compliance (i.e., more than
75% intake of the prescribed doses).
At our set-up, ECT is often considered in patients of schizophrenia,
who have orid positive symptoms, are violent or agitated, have
catatonic symptoms and have comorbid depressive or manic symp-
toms. If the patients have orid positive symptoms and are very violent,
aggressive, have catatonic symptoms and have depressive symptoms
along with suicidality, they are usually started on ECT prior to
institution of clozapine or are started on ECT along with starting of
clozapine. Whereas patients who have orid positive symptoms with-
out aggression or violence, those who have depressive symptoms
(without associated suicidality) are usually started on clozapine rst
and if they donot respond to clozapine or worsen clinically while the
dose of clozapine is being increased are considered for augmentation
with ECT later on. Accordingly, various combinations of treatment
sequence which emerge are: ECT started prior to starting clozapine,
ECT started along with clozapine and ECT started after clozapine.
2.3. Data extraction
For this study, case notes of all the patients who received ECT
during the period of January 2001 to June 2014 were reviewed to
identify patients with treatment-resistant schizophrenia/schizoaec-
tive disorder who were administered ECT in combination with
clozapine.
Socio-demographic and clinical data were extracted. Additionally,
data pertaining to the rating on various symptom-scales prior to
starting clozapine or ECT (whichever was initiated later), and after
completion of the index course of ECT were extracted. If a patient had
received maintenance ECT, symptom ratings at the end of the main-
tenance ECT course and other follow-up data was also extracted.
2.4. Analysis
The Statistical Package for the Social Sciences Version 14 (SPSS-14)
was used for analysis. Frequencies with percentages were calculated for
S. Grover et al. Psychiatry Research 249 (2017) 349353

Table 1 The mean age of onset of psychiatric illness was 21.9 (SD-6.8) years
Socio-demographic and Clinical profile of patients on clozapine-ECT combinations. and mean duration of illness at the time of administration of combined
treatment was 93.8 (SD-69.5) months.
Variable Whole group (N=59)

Mean (SD)/Frequency (%) 3.3. Treatment sequence

Age (in years) 29.77 (9.48) [Range: 1854]
Sex Based on the initiation of the two interventions, three types of
Male 37 (62.7%) combinations were noted: both ECT and clozapine started together
Female 22 (37.3%) (when second intervention was started within a period of less than 2
Education (in years) 10.33 (4.15) [Range: 018]
weeks of starting of rst intervention), ECT followed by clozapine
Marital status
Single 44 (74.6%) (dierence between starting of two interventions more than 2 weeks)
Married 15 (27.4%) and clozapine followed by ECT (dierence between starting of two
Occupation interventions more than 2 weeks). In 16 (27%) patients ECT was
Unemployed 35 (59.3%) started prior to starting of clozapine, in 21 (36%) patients clozapine
Housewife 17 (28.8%)
Currently working 7 (11.9%)
was followed by ECT and in 22 (37%) patients both the interventions
Income (in Indian Rupees.) were started together. Of the 21 patients in whom clozapine was
< 6000 13 (22%) followed by ECT, in 13 patients ECT was administered after a trial of 12
> 6000 46 (78%) weeks of clozapine treatment, in those who had shown minimal or
Living arrangement
partial response to clozapine. These patients have been referred to as
Nuclear 47 (79.7%)
Extended/joint 12 (20.3%) the clozapine-refractory group.
Background
Urban 36 (61%)
3.4. ECT prole
Rural 23(39%)
Psychiatric diagnosis
Paranoid schizophrenia 29 (49.2%) As shown in Table 1, the mean number of ECT treatments was
Undierentiated schizophrenia 21 (35.6%) 13.95 (SD-7.67) with a range of 545, with 3 patients receiving
Catatonic schizophrenia 3 (5.1%) maintenance ECT treatment. Other details of the ECT procedures are
Schizoaective disorder 5 (8.1%)
Psychosis NOS 1 (1.7%)
depicted in Table 1.
Age of onset of psychiatric illness (in 21.9 (6.8)
years)
3.5. Eectiveness of treatments
Duration of psychiatric illness (in 93.8 (69.5) [Range: 3288]
months)
No of adequate antipsychotic trials pre- 3.16 (1.38) [Range 17] The Positive and Negative Syndrome Scale for schizophrenia
clozapine (PANSS) was used to rate the change in psychopathology in 53
Clozapine dose (in mg) 287.5 (100.1) [Range: 75 patients. For all the 3 treatment sequences, pre-treatment PANSS
550]
refers to the time point at which the combination treatment was
Number of ECTs 13.95 (7.67) [Range 545]
First ECT (post clozapine) charge(in 199.92 (186.91) [Range 48 instituted and post-treatment PANSS refers to the time when ECT
milli Coulombs) 707] course was stopped completely or prior to consideration of main-
Mean charge (in milli Coulombs) 319.5 (180.4) [Range 92.3 tenance ECT. As shown in Table 2, there was signicant reduction in
661.7] the PANSS positive, negative and general psychopathology and total
Mean motor seizure duration (in 37.35 (9.84) [Range 18.23
seconds) 65.16]
scores following treatment. Overall there was reduction in PANSS score
by 26.78 (SD-13.31; range 265) points and in terms of percentage
reduction, there was mean reduction in PANSS score by 31.65 (SD-
the categorical variables. Mean and standard deviation were computed
12.92; range 2.8664) percent. On further analysis it was evident that
for the continuous variables. Comparisons were done by using t-tests
of the 53 patients rated on PANSS, 32 (60%) patients had more than
and Chi-square tests. Correlations were examined by computing
30% reduction in PANSS scores. When the eectiveness was evaluated
Pearson's Product Moment Correlation or Spearman's Rank
in terms of more than 20% reduction in PANSS scores, 81% (43 out of
Correlation coecients.
53) scored above the cut o. There was no signicant dierence in the
percentage reduction of PANSS score between paranoid and undier-
3. Results entiated schizophrenia patients. Similarly the response on PANSS was
not signicantly dierent between the 3 treatment sequence groups.
3.1. Sociodemographic prole Five patients were rated on Bush Francis Catatonia Rating scale
(BFCRS) because of predominant catatonic symptoms and all these
During the study period 864 patients received ECT, of whom 59
patients had received combinations of clozapine and ECT. The socio- Table 2
demographic and clinical prole of the patients is shown in Table 1. Effectiveness of combined clozapine-ECT treatment.
The mean age of the study sample was 30 (SD-9.48) years and the
Variable Pre-treatment Post-treatment Paired t-test (p
mean duration of years of education was 10.33 (SD-4.15) years.
value)
Majority of the patients were male, single, unemployed, had an income
of more than 6000 Indian rupees, and were from nuclear families of Positive symptom score 23.9 (6.1) 14.2 (5.6) 11.57(p < 0.001)
urban background. [range: 1140] [range 730]
Negative symptom score 18.5 (5.9) 14.2 (4.8) 7.90 (p < 0.001)
[range: 841] [range 728]
3.2. Clinical prole General psychopathology 40.9 (7.8) 27.6 (6.3) 13.6 (p < 0.001)
[range 2865] [range 1841]
Total PANSS Score 83.11 (15.96) 56.23 (13.28) 14.22 (p < 0.001)
The most common diagnosis for which the combined treatment was
[range: 58 [range 3586]
used was paranoid schizophrenia followed by undierentiated schizo- 125]
phrenia.

351

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S. Grover et al.
patients had more than 50% reduction in symptoms. The three patients
with schizoaective disorder did not fare as well. None of them had
more than 30% reduction in PANSS scores, with reduction in PANSS
scores ranging from 21% to 29% only.
However, on the whole when 30% reduction in scores across the
dierent scales was considered as a cut-o score, 63% of patients
(irrespective of diagnosis) responded to the combined treatment.
In the clozapine-refractory patient group (13 patients), nine
patients (69%) had more than 30% reduction in PANSS scores, and
when the eectiveness was considered as more than 20% reduction in
PANSS, 85% (11 out of 13) responded to the augmentation of clozapine
treatment with ECT.
3.6. Reason for stopping ECT
In majority of the patients (N=49; 83%), ECT was stopped because
the response over the last 2 ECT had reached a plateau. However, in
eight patients (13%) ECT was stopped because of minimal response; in
one patient ECT was terminated prematurely because of complications,
and in another one ECT was stopped because of withdrawal of consent
by the patient.
3.7. Side-eects related to ECT
In terms of immediate side eects, 10 (17%) patients had transient
rises in blood pressure during the ECT procedure, which required the
use of esmolol. One patient experienced transient bradycardia. Two
(3%) patients experienced delirium after one of the ECT treatment;
both were receiving clozapine in the doses of 250 mg/day or more.
Prolonged seizure ( > 1 min of motoric seizure) was seen in 4 patients
(7%). Three out of the 4 patients who developed prolonged seizures
were receiving clozapine in the doses of 250 mg/day or more. Eight
(13.6%) patients reported mild cognitive impairment while receiving
ECT.
3.8. Correlates of response
A signicant negative association was noted between the number of
previous adequate antipsychotic trials and level of response with
clozapine-ECT combination (Pearson's product moment correlation
coecient 0.353; p=0.010). There was no association between the
percentage reduction in PANSS scores and age, age at onset, duration
of illness and duration of delay in starting clozapine.
3.9. Long term follow-up
Long term follow-up data were available for 47 patients; the
remaining 12 patients did not follow-up after the completion of ECT
course or discharge from the hospital. The mean duration of follow-up
was 29.7 (SD 32.3; range: 1120) months. Thirty two patients (52%)
had followed-up for more than a year. The majority of these patients
(34 of the 47 or 72%) continued taking clozapine and remained
relatively well (i.e., maintained the symptomatic improvement gained
or improved further). Additional ECT treatments had been required in
three patients.
4. Discussion
This study attempted to assess the eectiveness and safety of the
combination of clozapine and ECT among patients with TRS.
Retrospective study design and lack of a control group restricts the
extent to which its results can be generalized. Nevertheless, given
limited evidence from randomized-controlled trials on the subject, such
studies still have some value. Moreover, the comparatively large sample
of patients, the inclusion of a clozapine-refractory group and the data
on long-term follow-up add to the usefulness of its ndings.
352
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Psychiatry Research 249 (2017) 349353
The ndings of the current study were in accordance with those of
earlier studies on many aspects of the use of the clozapine-ECT
combination in TRS. The number of ECT treatments used in the
present study was comparable to that used in previous studies
evaluating the eectiveness of this combination (Frankenburg et al.,
1993; Cardwell and Nakai, 1995; Benatov et al., 1996; Kales et al.,
1999; James and Gray, 1999; Kho et al., 2004; Masoudzadeh and
Khalilian, 2007; Flamarique et al., 2012; Petrides et al., 2015).
However, the mean dose of clozapine used in this study was lower
than many of the other studies (Kho et al., 2004; Biedermann et al.,
2011; Petrides et al., 2015). Existing data also suggest that lower doses
of clozapine are generally used among Indian patients (Srivastava et al.,
2002; Grover et al., 2015b).
More importantly, the ndings of the present study indicated that
the combination of clozapine and ECT was eective in patients with
TRS who did not respond to several antipsychotics. When the cut-o of
> 30% reduction in the scores across the dierent symptom-scales was
considered as an indicator of response to treatment, 63% of patients
responded to the combined treatment. A somewhat similar response
(69%) was also obtained in the clozapine-refractory group. There is lot
of heterogeneity in the literature in terms of evaluation of eectiveness
of combined clozapine and ECT. Studies have often not reported the
exact sequence of introduction of the two treatments, and whether the
patients fullled the criteria or TRS only, or of clozapine-refractoriness
(Kupchik et al., 2000; Braga et al., 2005; Havaki-Kontaxaki et al., 2006;
Tranulis et al., 2006). Accordingly, the present study attempted to
clearly identify the sequence of use of these two treatments and the
response rates in TRS as well as the clozapine-refractory sub-groups.
The results show response rates with concurrent use of the combina-
tion and with clozapine followed by ECT were comparable to the
response rates (2771%) reported for the combined treatment in a
number of previous studies (Frankenburg et al., 1993; Cardwell and
Nakai, 1995; Benatov et al., 1996; Kales et al., 1999; Kho et al., 2004;
Masoudzadeh and Khalilian, 2007; Koen et al., 2008; Flamarique et al.,
2012; Petrides et al., 2015; Lally et al., 2016).
Previous reports have documented rare untoward eects of the
clozapine-ECT combination such as cardiac arrhythmias, prolonged
seizures, delirium and cardiomyopathy (Masiar and Johns, 1991; Bloch
et al., 1996; Kumar et al., 2003; Grubisha et al., 2014; Biedermann
et al., 2011; Manjunatha et al., 2011). Although the prevalence of
serious side eects was low among patients of this study, delirium and
prolonged seizures were observed in about 10% of the patients. Both
were associated with higher than usual doses ( > 250 mgs/day) of
clozapine. The association with delirium, possibly because of the
anticholinergic properties of clozapine, has been reported with high
doses of clozapine when used with ECT (Kumar et al., 2003;
Manjunatha et al., 2011; Raedler, 2007). Similarly, prolonged seizures
have been reported with the clozapine-ECT combination, though the
link with higher doses has not been clearly established (Cardwell and
Nakai, 1995; Bloch et al., 1996; Poyurovsky and Weizman, 1996; Koen
et al., 2008). However, the occurrence of prolonged seizures with high
doses was not entirely unexpected, given that the risk of seizure
increases with higher doses of clozapine (Devinsky et al., 1991;
Greenwood-Smith et al., 2003; Grover et al., 2015c). The most
common side-eect of the clozapine-ECT combination in this study
was, however, a transient rise in blood pressure while administering
ECT. This has not been reported before. Overall, the current study
demonstrated that the clozapine-ECT combination is a relatively safe
one provided doses of clozapine are kept low and adverse eects are
carefully monitored and promptly treated.
Polypharmacy is frequently practiced in TRS and an unnecessary
delay in starting clozapine is also common in routine clinical practice
(Taylor et al., 2003; Howes et al., 2012; Kristensen et al., 2013;
Wheeler et al., 2014; Grover et al., 2015b). In this study, a signicantly
better response to combination of clozapine and ECT was associated
with fewer previous antipsychotic trials. This suggests that patients
S. Grover et al.
who do not respond to two adequate trials of non- clozapine anti-
psychotics should be treated with clozapine without delay.
Additionally, if patients do not respond to an adequate trial of
clozapine, the addition of ECT may prove useful as an option for
augmentation of clozapine non-response.
There is limited long term follow-up data of patients who are
treated with combinations of clozapine and ECT (Bhatia et al., 1998;
Kho et al., 2004; Flamarique et al., 2012; Kales et al., 1995, 1999). In
general, studies have followed up patients for short durations, and have
reported sustained improvement only in a small proportion of patients.
On the other hand, results of the current study indicated that about
two-thirds of the patients maintain the improvement they achieve with
combined treatment, and do well if they continue to take clozapine.
To conclude, the results of this study have further endorsed the
eectiveness, safety and long-term benets of the clozapine-ECT
combination in TRS and clozapine-refractory schizophrenia. There is
no doubting, however, that much more high-quality evidence is
required to conclusively establish the usefulness of this combination
in resistant schizophrenia.
Statement of interest
None to declare.
Acknowledgement
None.
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