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Continuation Electroconvulsive Therapy for Patients With Clozapine-Resistant Schizophrenia

A Pilot Study

Braga, Raphael J. MD; John, Majnu PhD; Schooler, Nina R. PhD; Bailine, Samuel H. MD; Malur, Chitra MD; Mendelowitz, Alan MD; Petrides, Georgios MD

doi: 10.1097/YCT.0000000000000588
Original Studies

Objectives The risk of relapse after a successful acute course of treatment is a clinical challenge in electroconvulsive therapy (ECT) practice, particularly in patients with a history of marked resistance to previous treatments. Research suggests that a gradual decrease of ECT or its long-term continuation might be the best strategy. Notwithstanding, current studies do not address the role of continuation ECT in the truly refractory cases, that is, the clozapine-resistant patients. Our group published a randomized controlled trial of ECT augmentation of clozapine in clozapine-resistant patients with schizophrenia, where the augmentation was vastly superior in efficacy for the acute treatment. The aim of the current study is to evaluate the efficacy of continuation ECT for patients who showed response to the combination of acute ECT and clozapine for treatment-resistant schizophrenia.

Methods Continuation ECT was offered to all patients who completed the acute study and who met response criterion. We followed a tapered schedule of 4 weekly ECT sessions, followed by 4 ECT sessions every 2 weeks and 2 monthly ECT sessions for a total of 10 sessions.

Results Patients sustained the gains achieved with the acute course of ECT, and no individual patient presented with clinically relevant worsening of symptoms. Moreover, the long-term use of ECT was not associated with added adverse effects.

Conclusions This is an open pilot study with a small sample size, and results should be interpreted accordingly, but this report offers a relevant starting point for much needed future studies.

From the Division of Psychiatry Research, The Zucker Hillside Hospital, Northwell Health, Glen Oaks; and The Feinstein Institute for Medical Research, Manhasset, NY.

Received for publication October 25, 2018; accepted January 4, 2019.

Reprints: Raphael J. Braga, MD, The Zucker Hillside Hospital, Northwell Health, 7559 263rd St, Glen Oaks, NY 11004 (e-mail:

G.P. has grants from the National Institute of Mental Health, the National Institute of Aging, and Astra Zeneca. For the remaining authors, no conflicts of interest were declared.

Online date: April 10, 2019

Electroconvulsive therapy (ECT) is regarded as the treatment of choice for severe mental disorders and when other treatment modalities such as psychotherapy and pharmacotherapy have failed. Extensive literature supports the robust efficacy of ECT in affective disorders. Major depression is the most common indication for which ECT is used, especially in North America and in Western countries.1 Although available data indicate that ECT is an effective acute treatment of schizophrenia,2 including treatment-resistant cases,3,4 the number of controlled studies is still small, and clinicians are less inclined to recommend ECT for this population. One often cited reason is the paucity of published data on the long-term efficacy of ECT in a chronic illness such as schizophrenia.5

The risk of relapse after a successful acute course of treatment is a clinical challenge in ECT practice. Longitudinal studies, mostly with major depression, report substantial relapse rates, That is especially true if maintenance treatment in the form of either pharmacotherapy6 or continuation ECT (C-ECT)7 is not administered. Available literature is scant, and there are no C-ECT treatment guidelines published. Research on C-ECT strategies suggests that a gradual decrease of ECT or its long-term continuation might be the best strategy, particularly in patients with a history of marked resistance to previous treatments. The PRIDE study is one of the few large and well-designed trials on the topic. Its results indicate that the combination of ECT and pharmacotherapy is superior to medication alone in preventing relapse after a successful course of ECT for major depression.8

Most available reports concerning C-ECT in schizophrenia are retrospective. Results suggest that C-ECT is associated with sustained clinical improvement with minimal adverse effects. To our knowledge, only one prospective controlled study evaluated the role of C-ECT in schizophrenia. Chanpattana et al9 conducted a 2-phase study. In the first phase, 114 patients with treatment-resistant schizophrenia (TRS) received acute treatment with bilateral ECT and a first-generation antipsychotic, flupenthixol. Fifty-eight patients met stringent remitter criteria and were included in the single-blind 6-month continuation treatment study (phase II). Patients were randomized to 3 treatment groups: combined C-ECT and flupenthixol, C-ECT alone, and flupenthixol alone. After 6 months of continuation treatment, relapse rates were 40% for the combination group as opposed to 93% for both other monotherapy groups. Notwithstanding the interesting results, this study has not been replicated and does not answer questions regarding the role of C-ECT in the truly refractory cases of schizophrenia, that is, the clozapine-resistant patients.

Clozapine is the only antipsychotic with an indication for TRS, but more than 70% of these cases fail to benefit from this drug. Our group recently published the results from a randomized controlled trial of ECT augmentation of clozapine in clozapine-resistant patients with schizophrenia.4 In our sample, 19 of 39 patients responded to an 8-week long acute course of bilateral ECT by showing at least 40% improvement in their psychotic symptoms as measured by the psychosis items of the Brief Psychiatric Rating Scale (BPRS). However, the longevity of the improvement offered by an acute trial of ECT in patients with clozapine-resistant schizophrenia is not well understood. Results from a few case reports10 and chart reviews11 indicate that C-ECT may be helpful and safe in maintaining acute results in clozapine-treated patients. One prospective study describes C-ECT being successful and safe in 3 of 5 clozapine-treated patients. Patients were followed for up to 12 weeks, but no further information is available.12

Because of the marked severity and the chronic nature of the symptoms in our study cohort, as well as the results of the previously mentioned study by Chanpattana et al, we expected a high relapse rate after discontinuation of acute ECT. Therefore, we offered an open-label, 6-month C-ECT option for all participants who showed response to ECT. The aim of the current study is to evaluate the efficacy of C-ECT for patients who showed response to the combination of acute ECT and clozapine for TRS.

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The sample was recruited from completers of a randomized, controlled, single-blind, National Institute of Mental Health–sponsored study in which we evaluated the efficacy of ECT as an augmentation strategy for clozapine-resistant schizophrenia.4 Methods are described in detail elsewhere.4 Main inclusion criteria were as follows: diagnosis of schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria; age 18 to 60 years; duration of illness of more than 2 years; resistance to at least 2 antipsychotics; clozapine resistance defined by a confirmed therapeutic blood level of clozapine and current psychotic symptoms, specifically a baseline BPRS score of at least moderate (score of ≥4) on 1 of the 4 psychotic items (hallucinatory behavior, suspiciousness, conceptual disorganization, and unusual thought content) of the psychotic symptom subscale (BPRS-PS), or a score of 12 on these 4 items combined; and a Clinical Global Impressions (CGI)–severity rating of at least moderate (score of ≥4). Patients were randomized to receive 8 weeks of ECT in addition to clozapine or to continue with clozapine treatment alone. Patients in the pharmacotherapy arm who did not respond after 8 weeks crossed over to ECT and received the combination treatment for 8 weeks. Using the response criterion of a 40% reduction in the BPRS-PS, we reported response rates of 50% for the single-blind phase of the study and 48% for the crossover phase.

For the current study, C-ECT was offered to all patients who completed either phase of the acute study and who met response criterion. The continuation phase lasted for up to 24 weeks during which patients received ECT with the same treatment parameters as in the acute phase, that is, bilateral (bifrontotemporal) placement at 1.5× threshold. Anesthetic medications used were methohexital (0.5–1.5 mg/kg) and succinylcholine (0.5–1 mg/kg). We followed a tapered schedule of 4 weekly ECT sessions, followed by 4 ECT sessions every 2 weeks and 2 monthly ECT sessions for a total of 10 sessions in 6 months, mirroring a C-ECT study in major depression by the CORE group.7 Medication regimen, including clozapine, remained the same as in the acute phase, and no additional psychotropic medications were allowed.

Psychopathology ratings were performed at baseline (end of acute phase), before each ECT and 1 week after the last ECT session. As a secondary outcome, a neuropsychological battery was performed at 3 time points: baseline and week 9 of the acute phase, as well as after the last ECT session of the continuation phase. The battery included the standard and modified Mini-Mental State Examination, the Rey Auditory Verbal Learning Test, the paired-word and story-recall measures subtests 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.

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Statistical Analysis

Because of the small sample size (n = 14), we consider the continuation phase reported in this article as an open-label pilot study. In line with guidelines for the analysis and reporting of pilot studies, the emphasis was not on hypothesis testing, and hence, P values are not presented for the analysis of the primary and secondary outcomes; only descriptive statistics (means, SEs) are presented. P values are reported to compare the demographics between the 2 groups (not in the continuation group versus in the continuation group) presented in Table 1. Differences in patient characteristics between groups in Table 1 were examined using χ2 analysis for categorical variables, and independent-samples t test or Wilcoxon rank sum test for continuous variables. The primary outcomes for the continuation phase were the longitudinal positive symptom score obtained from the BPRS-PS (anchored version) and the severity measure of the CGI scale. Least square means and SEs obtained from a mixed-models analysis are the descriptive statistics reported for the primary outcomes and plotted in Figures 1 and 2. The secondary outcome was neurocognitive effects of ECT. Raw means and SEs for neurocognitive measures at phase 1 baseline, continuation-phase baseline, and the last visit in the continuation phase are presented in Figures 3 and 4.











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Continuation ECT was offered to 19 patients who met response criteria, and 14 patients agreed. Those who refused did so because they did not have adequate support network to facilitate outpatient ECT and did not want to prolong inpatient stay. One patient did not want to have further ECT because he felt that he did not need the treatment anymore.

Sociodemographic and clinical characteristics of the patients are presented in Table 1. For illustration purposes, we include the characteristics of subjects who did not enroll in the continuation phase. When compared with the characteristics of those who did enroll, no significant differences were noted.

Six (42.9%) of the 14 patients completed the 6-month study (10 C-ECT treatments). The remaining subjects (57.1%) received between 4 and 7 continuation treatments. None of the 14 patients had relapsed at the time they stopped C-ECT. Among the patients who received C-ECT, the mean BPRS-PS was 17.0 (±0.9) before the acute course of ECT (Fig. 1). Their mean BPRS-PS scores were 7.7 (±0.9) at continuation baseline and 9.4 (±0.9) at the end of the study for the total sample, and 9.6 (±1.0) for the completers. Similar trends were observed with the CGI (Fig. 2). Mean CGI scores were 5.07 (±0.3) before the acute course of ECT, 3.71 (±0.3) at C-ECT baseline, and 3.64 (±0.3) at the last observation for total sample, and 3.61 (±0.3) for completers. All 8 patients who received C-ECT for less than 6 months stated that they felt well and there was no further need for ECT, or could not continue for practical reasons, mostly lack of social support as outpatients.

Visual inspection of cognitive measures suggested stability, or possibly some degree of improvement of neuropsychological functions during the continuation phase, as compared with C-ECT baseline (Figs. 3 and 4).

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Although ECT was first used in a patient diagnosed as having schizophrenia, its use was dramatically reduced after the advent of psychopharmacology in the 1950s. Antipsychotic agents are effective and overall safe for many patients with schizophrenia. Patients who are resistant to the beneficial effects of first- and second-generation antipsychotics can still benefit from clozapine, which remains the only agent shown to be effective in TRS. More recently, the recognition that a substantial subgroup of TRS patients does not experience significant improvement with clozapine has led to scientific interest in possible augmentation strategies. A large number of pharmacological agents, primarily second-generation antipsychotics, have been used for this purpose, but none have shown particular promise.13 Electroconvulsive therapy is the treatment indicated for refractory conditions, and in fact, work from our research group showed that it is markedly effective as an acute treatment of clozapine-refractory schizophrenia, when used as an augmentation strategy.4

In this pilot study, we suggest that ECT may also be effective as a continuation strategy to prevent symptomatic relapse after a successful acute course of ECT. During the 6-month maintenance period, our patients sustained the gains achieved with the acute course of ECT and no individual patient presented with clinically relevant worsening of symptoms. Moreover, the long-term use of ECT in this cohort was not associated with added adverse effects. In fact, some subjects experienced some improvement in cognition during the study period. This is likely due to the progressively lower frequency of ECT sessions administered and, for some patients, the improved level of functioning and cooperation with cognitive testing. The pattern of improved cognition in the maintenance phase is comparable with that reported in depression studies. Interestingly, we observed a potential small increase in psychopathology as measured by the BPRS-PS toward the end of the 6-month period. We speculate that this possible pattern is due to the increased interval between sessions. As noted earlier, one limitation of this report is that we followed an inflexible, fixed, tapered schedule of treatments similar to depression studies published at that time (CORE C-ECT study).7 Such a schedule does not provide the possibility for rescue treatments when needed, which is a common clinical practice in ECT in general and has been shown to be effective in depression (PRIDE).8 Research suggests that different patients' characteristics can influence the interval of C-ECT sessions.14

The current report is also limited by unmasked ratings, the small sample size, and the lack of a control arm, which in effect did not allow for statistical analysis of clinical effects. Our sample size was further limited by a notable noncompletion rate (8/14) of patients. Many possible reasons can be suggested to explain the low retention rates, such as stigma or difficulties related to logistics in bringing patients to the ECT clinic. Also, although no marked clinical worsening was observed at the last observation of all patients, it is possible that the aforementioned inflexible schedule could have led to relapses unbeknownst to our research team. We therefore suggest that it would be relevant to address these questions in future studies, for instance, by means of evaluation of patients' perceptions and expectations regarding the treatment. It is possible that additional interventions such as psychoeducation could lead to improved retention. Moreover, it would be important to evaluate the effects of flexible ECT schedules on retention rates.

Notwithstanding, given the dearth of available data on C-ECT in schizophrenia, the results of this report offer a relevant starting point for much needed future studies. Besides replication in larger samples, randomized trials are needed to study the value of continuation and maintenance ECT in those patients who responded to an acute course of ECT augmentation to clozapine, as well as studies to determine the optimal frequency of C-ECT.

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electroconvulsive therapy; clozapine; schizophrenia

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