ECT in Ultra-resistant Schizophrenia

Study Overview
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Brief Summary
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The effects of the ECT in schizophrenia ultra-resistant were studied in short times (4-6 months in most studies with follow-up). The literature identified a high relapse rate of 32% in the weeks to months after ECT discontinuation. The use of the ECT in the prevention of the relapse is partially known. In an empirical way, experts recommend protocols of prevention of the relapse going from 6 to 12 months. Nevertheless, the profit of a long cure (12 months) compared with a short cure (6 months) was never determined. Therefore, the investigators decided to lead a prospective randomized controlled study in order to compare the response rates between the two strategies of clozapine and ECT combinations applied to URS patients. The treatment consisted either in a short therapy of six months or a longer course of therapy of twelve months. To the investigators' knowledge, it is the first study which compares two ECT strategies (both the short duration and the longer one) for the treatment of URS patients.

Official Title
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Clinical Trial Comparing Two Electroconvulsive Therapy (ECT) Application Schemas in Ultra-resistant Schizophrenia

Conditions
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Schizophrenia, Electroconvulsive Therapy

Intervention / Treatment
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* Device: Electroconvulsive therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with URS: patients who continue to experience persistent positive psychotic symptoms: item score of 4 (moderate) on at least two of four positive symptoms on the BPRS (grandiosity, suspiciousness, hallucinations and unusual thoughts), current presence of at least moderately severe illness on the total BPRS-18 (45) and a score of 4 (moderate) on the CGI-S, despite a period of clozapine therapy of at least 6 weeks with a plasma concentration of 350 ng/ml and at least two unsuccessful previous treatment trials with conventional or atypical antipsychotic drugs from two distinct families at a dose 600 mg of chlorpromazine equivalents. Age: from 18 to 55 Patients with stable treatments for at least 8 weeks (antipsychotics, mood stabilizers and antidepressants). Participants who gave their informed, written consents and agreement of their guardian for the patients under guardianship Patients deprived of liberty if they gave their informed, written consents Exclusion Criteria: Current affective episode according to DSM-5 criteria; ECT within (the last) 6 months; Unstable epilepsy ; severe neurological or systemic disorder that could significantly affect cognition, behavior, or mental status (other than late dyskinesia or neuroleptic-induced parkinsonism); Severe substance use disorders (other than nicotine or caffeine) according to DSM-5 criteria. Concomitant use of antiepileptics and benzodiazepines apart from lamotrigine Women of childbearing age with no adequate contraception, pregnant or lactating women; Patients having contraindications to etomidate or any of its excipients; Patients having contraindications to neuromuscular blocking agents; Patients participating or having participated in an interventional clinical trial within 30 days prior to the inclusion visit;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A multicentric, prospective, random-assignment study incorporating both non-blinded treatment and blinded assessment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Short ECT arm<br>In the short arm, bitemporal ECT is administered twice a week during the first 6 weeks. Afterwards, it is administered once a week during 4 weeks. After that, the patients will have one ECT every 3 weeks during 6 weeks. Lastly, patients will receive one ECT each month during 2 months. | Device: Electroconvulsive therapy<br>* Electroconvulsive therapy is administered through electrodes positioned bilaterally (for quicker efficacy) on the frontotemporal region. The stimulation dose is determined by titration method, during the first ECT session. The dose for therapeutic stimulation will be twice the seizure threshold. This dose may be increased as the crisis does not meet the effectiveness criteria, as is recommended. For patients undergoing ECT, an intravenous injection of etomidate (between 0.1 and 0.7 mg/kg) and suxamethonium chloride (0.8 and 1.2 mg/kg) is performed. The required doses are adapted according to each patient by the anaesthetist and they are documented in the patients' files. A mixture of etomidate and propofol can be used in second-line or just propofol in third-line (no more than 2mg/kg).<br>|
| Active Comparator: Long ECT arm<br>In the long arm, bitemporal ECT is administered twice a week during the first 12 weeks. Afterwards, it is administered once a week during 8 weeks. After that, the patients will have one ECT every 3 weeks during 12 weeks. Lastly, patients will receive one ECT each month during 4 months. | Device: Electroconvulsive therapy<br>* Electroconvulsive therapy is administered through electrodes positioned bilaterally (for quicker efficacy) on the frontotemporal region. The stimulation dose is determined by titration method, during the first ECT session. The dose for therapeutic stimulation will be twice the seizure threshold. This dose may be increased as the crisis does not meet the effectiveness criteria, as is recommended. For patients undergoing ECT, an intravenous injection of etomidate (between 0.1 and 0.7 mg/kg) and suxamethonium chloride (0.8 and 1.2 mg/kg) is performed. The required doses are adapted according to each patient by the anaesthetist and they are documented in the patients' files. A mixture of etomidate and propofol can be used in second-line or just propofol in third-line (no more than 2mg/kg).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The response rate (a 30% decrease in the Positive and Negative Syndrome Scale (PANSS)) at 15th month | The response rate (a 30% decrease in the PANSS, ranging from 30, the minimum, to 210, the most severe score) at 15th month | three months after the end of the treatment (i.e. 9 and 15 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The response rate (a 30% decrease in the Brief Psychiatric Rating Scale (BPRS)) | The response rate (a 30% decrease in the BPRS, ranging from 18, the minimum, to 126, the most severe score) at 15th month. | three months after the end of the treatment (i.e. 9 and 15 months) | 
| The response rate (a 30% decrease in the BPRS) at different times of the study | The response rate (a 30 % decrease in the BPRS) at 2, 4, 6 and 12 months. | 2, 4, 6 and 12 months | 
| Response rate (a 30% decrease in the PANSS) at different times of the study | The response rate (a 30 % decrease in the PANSS) at 2, 4, 6 and 12 months. | 2, 4, 6 and 12 months | 
| Neuropsychological assessment- MMSE | The scores and variations of the Mini Mental Status Examination (MMSE) at -1, 6 and 15 months. | -1, 6 and 15 months | 
| Neuropsychological assessment- SSTICS | The scores and variations of the Subjective Scale To Investigate Cognition In Schizophrenia (SSTICS, scores ranging from 0 to 84, the most severe score) at -1, 6 and 15 months. | -1, 6 and 15 months | 
| Neuropsychological assessment- Grober and Buschke test | The scores and variations of the test of Grober and Buschke at -1, 6 and 15 months. | -1, 6 and 15 months | 
| Neuropsychological assessment- test of doors | The scores and variations of the test of doors at -1, 6 and 15 months. | -1, 6 and 15 months | 
| Neuropsychological assessment- test of d2 | The scores and variations of the test of d2 at -1, 6 and 15 months. | -1, 6 and 15 months | 
| Neuropsychological assessment - figure de Rey test | the scores ans variations of the test of  figure de Rey at -1, 6 and 15 months. | -1, 6 and 15 months | 
| Other clinical assessment- HAMD-21 | The scores and variations of the Hamilton Rating Scale-21 items (HAMD-21, scores ranging from 0 to 64, the most severe score) at day 1 and 2, 4, 6, 9, 12 and 15 months. | day 1 and 2, 4, 6, 9, 12 and 15 months | 
| Other clinical assessment-YMRS | The scores and variations of the Young Mania Rating Scale (YMRS, scores ranging from 0 to 60, the most severe score) at day 1 and 2, 4, 6, 9, 12 and 15 months. | day 1 and 2, 4, 6, 9, 12 and 15 months | 
| Other clinical assessment-GAF | The scores and variations of the Global Assessment Functioning (GAF, scores ranging from 0 to 100, the best score) at day 1 and 2, 4, 6, 9, 12 and 15 months. | day 1 and 2, 4, 6, 9, 12 and 15 months | 
| Other clinical assessment-MOAS | The scores and variations of the Modified Overt Aggression Scale (MOAS, scores ranging from 0 to 100, the most severe score) at day 1 and 2, 4, 6, 9, 12 and 15 months. | day 1 and 2, 4, 6, 9, 12 and 15 months |