Electroconvulsive Therapy Versus Aripiprazole Addition to Clozapine in Patients with Clozapine-Resistant Symptoms (EMECLO): A Protocol of a Single-Blind, Multicenter, Randomized-Controlled Feasibility Trial

Abstract

Background Currently, guidance on the most effective treatment for patients with clozapine-resistant schizophrenia-spectrum disorders (SSD) is lacking. While augmentation strategies to clozapine with aripiprazole and electroconvulsive therapy (ECT) have been demonstrated to be effective in patients with clozapine-resistant schizophrenia spectrum disorders (CRS), head-to-head comparisons between these addition strategies are unavailable. We therefore aim to examine the feasibility of a larger randomized, single-blind trial comparing the effectiveness, cost-effectiveness, and safety of aripiprazole addition vs. ECT addition in CRS.

Methods In this multi-center, randomized, single-blind feasibility study, the feasibility of recruiting 20 participants with CRS who will be randomized to either aripiprazole or bilateral ECT addition will be assessed. The main endpoint is the number of patients willing to be randomized. The number of screened individuals and reasons to decline participation will be recorded. Effects will be estimated for the benefit of the foreseen larger trial. To that end, differences between both arms in symptom severity will be assessed using blinded video assessments. In addition, tolerability (e. g., cognitive functioning), safety, quality of life, recovery, and all-cause discontinuation will be compared. The follow-up period is 16 weeks, after which non-responders will be given the option to switch to the other treatment.

Discussion Strengths of this feasibility trial include maintaining blinding with video assessment, a possibility to switch groups in case of non-response, and a broad set of outcome measures. Identification of factors contributing to non-participation and drop-out will generate valuable information on trial feasibility and may enhance recruitment strategies in a follow-up RCT.

Trial registration The study has been approved by the Medical Research Ethics Committee of the Amsterdam University Medical Center, location AMC, and was registered on 1 May 2022 in the EU Clinical Trials Register (EudraCT) under the trial name ‘EMECLO’ (2021–006333–19).

Keywords

schizophrenia - clozapine-resistant - clozapine-refractory - clozapine-resistant - clozapine - electroconvulsive therapy - ECT - aripiprazole

^# These authors contributed equally: Manouk den Toom, Laura Blanken, Jasper B. Zantvoord, Jurjen J. Luykx.

Publication History

Received: 22 February 2024

Accepted after revision: 21 May 2024

Article published online:
26 August 2024

• References

• 1 Charlson FJ, Ferrari AJ, Santomauro DF. et al. Global epidemiology and burden of schizophrenia: Findings from the Global Burden of Disease Study 2016. Schizophr Bull 2018; 44: 1195-1203
• 2 Brenner HD, Dencker SJ, Goldstein MJ. et al. At issue: Defining treatment refractoriness in schizophrenia. Schizophr Bull 1990; 16: 551-561
• 3 Conley RR, Kelly DL. Management of treatment resistance in schizophrenia. Biol Psychiatry 2001; 50: 898-911
• 4 Stroup TS, Gerhard T, Crystal S. et al. Comparative effectiveness of clozapine and standard antipsychotic treatment in adults with schizophrenia. Am J Psychiatry 2016; 173: 166-173
• 5 Okhuijsen-Pfeifer C, Huijsman EAH, Hasan A. et al. Clozapine as a first- or second-line treatment in schizophrenia: A systematic review and meta-analysis. Acta Psychiatr Scand 2018; 138: 281-288
• 6 Siskind D, Siskind V, Kisely S. Clozapine response rates among people with treatment-resistant schizophrenia: Data from a systematic review and meta-analysis. Can J Psychiatry 2017; 62: 772-777
• 7 Zheng W, Zheng YJ, Li X. Bin et al. Efficacy and safety of adjunctive aripiprazole in schizophrenia: Meta-analysis of randomized controlled trials. J Clin Psychopharmacol 2016; 36: 628-636
• 8 Siskind DJ, Lee M, Ravindran A. et al. Augmentation strategies for clozapine refractory schizophrenia: A systematic review and meta-analysis. Aust N Z J Psychiatry 2018; 52: 751-767
• 9 Dayabandara M, Hanwella R, Ratnatunga S. et al. Antipsychotic-associated weight gain: Management strategies and impact on treatment adherence. Neuropsychiatr Dis Treat 2017; 13: 2231-2241
• 10 Veerman SRT, Schulte PFJ, de Haan L. Treatment for negative symptoms in schizophrenia: A comprehensive review. Drugs 2017; 77: 1423-1459
• 11 Petrides G, Malur C, Braga RJ. et al. Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: A prospective, randomized study. Am J Psychiatry 2015; 172: 52-58
• 12 Sinclair DJM, Zhao S, Qi F. et al. Electroconvulsive therapy for treatment-resistant schizophrenia. Cochrane Database Syst Rev 2019; 3: CD011847
• 13 Barber S, Olotu U, Corsi M. et al. Clozapine combined with different antipsychotic drugs for treatment-resistant schizophrenia. Cochrane Database Syst Rev 2017; 3: CD006324
• 14 Lysaker PH, Vohs J, Hillis JD. et al. Poor insight into schizophrenia: Contributing factors, consequences and emerging treatment approaches. Expert Rev Neurother 2013; 13: 785-793
• 15 Lim C, Hernandez M, Gaona L. et al. Recruitment of Asian Americans with schizophrenia spectrum disorder for research participation: Barriers, strategies, and outcomes. Community Ment Health J 2021; 57: 490-501
• 16 American Psychiatric Association. et al. Practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry 2020; 177: 868-872
• 17 National Institute for Health and Care Excellence. et al. Psychosis and schizophrenia in adults: Prevention and management (Clinical guideline CG178). 2014
• 18 European Psychiatric Association. et al. Schizophrenia: Guideline for the treatment of patients with schizophrenia (EPA guidance on schizophrenia). 2015
• 19 Dutch Association for Psychiatry. Schizophrenia guideline. 2017
• 20 Dutch Association for Psychiatry, Schizophrenia Working Group. et al. Multidisciplinary guideline schizophrenia: Guideline for diagnosis, treatment, and guidance of adult patients with schizophrenia. 2017
• 21 World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. JAMA. 2013 310. 2191-2194
• 22 Shaffner K. Obtaining and using genetic information about mental disorders to advance behavioral genetics and improve patient satisfaction and recruitment. Behav Genet 2009; 39: 678-679
• 23 Andreasen NC, Carpenter WT, Kane JM. et al. Remission in schizophrenia: Proposed criteria and rationale for consensus. Am J Psychiatry 2005; 162: 441-449
• 24 Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261-276
• 25 Sheehan DV, Lecrubier Y, Sheehan KH. et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998; 59 Suppl 20: 22-33 ; quiz 34–57
• 26 Busner J, Targum SD. The clinical global impressions scale: Applying a research tool in clinical practice. Psychiatry (Edgmont) 2007; 4: 28-37
• 27 Addington D, Addington J, Maticka-Tyndale E. Assessing depression in schizophrenia: The Calgary depression scale. Br J Psychiatry Suppl. 1993: 39-44
• 28 Herdman M, Gudex C, Lloyd A. et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011; 20: 1727-1236
• 29 Nasreddine ZS, Phillips NA, Bédirian V. et al. The Montreal Cognitive Assessment, MoCA: A brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005; 53: 695-699
• 30 Tombaugh TN. Trail Making Test A and B: Normative data stratified by age and education. Arch Clin Neuropsychol 2004; 19: 203-214
• 31 Bennett-Levy J, Powell GE. The subjective memory questionnaire (SMQ). An investigation into the self-reporting of “real-life” memory skills. Br J Soc Clin Psychol 1980; 19: 177-188
• 32 McNaught M, Caputi P, Oades L. et al. Testing the validity of the recovery assessment scale using an Australian sample. Aust N Z J Psychiatry 2007; 41: 450-457
• 33 Peralta V, Cuesta MJ. Psychometric properties of the Positive and Negative Syndrome Scale (PANSS) in schizophrenia. Psychiatry Res 1994; 53: 31-40
• 34 Erasmus University Rotterdam. iMTA Productivity and Health Research Group. Manual iMTA Medical Cost Questionnaire (iMCQ). Rotterdam. 2018
• 35 Bouwmans C, Krol M, Severens H. et al. The iMTA productivity cost questionnaire: A standardized instrument for measuring and valuing health-related productivity losses. Value Health 2015; 18: 753-758
• 36 Whitehead AL, Julious SA, Cooper CL. et al. Estimating the sample size for a pilot randomised trial to minimise the overall trial sample size for the external pilot and main trial for a continuous outcome variable. Stat Methods Med Res 2016; 25: 1057-1073