Comparison of Maintenance ECT Versus Clozapine in Treatment-resistant Schizophrenia

Comparison of Maintenance ECT Versus Clozapine on Psychopathology and Cerebral Hemodynamics in Treatment-resistant Schizophrenia: A Randomized Controlled Trial

The proposed study will be conducted to compare the efficacy of maintenance ECT (M-ECT) vs Clozapine in treatment resistant schizophrenia (TRS) in terms of change in psychopathology measures and cerebral hemodynamics.

The proposed study is a prospective, randomized clinical trial in patients suffering from treatment-resistant schizophrenia (TRS) and will be conducted in the Department of Psychiatry, AIIMS, Bhubaneswar, over a period of 16 months. Sixty patients with TRS (TRRIP consensus criteria, 2017), fulfilling the inclusion and exclusion criteria will be recruited for the study. Written informed consent will be taken after explaining the objectives and procedure of the study in detail. The detailed history, relevant social-demographic and clinical data will be collected in a structured case record form (CRF). At baseline, PANSS will be administered to determine the severity of positive symptoms, negative symptoms, and general psychopathology, Global assessment of functioning (GAF), and CGI to determine the baseline severity of the illness and improvement with treatment and MoCA to assess change in cognitive impairment. Before starting the treatment, brain SPECT-CT will be done to measure baseline regional brain blood perfusion. The study cohort will be randomized into two treatment groups by computer-generated random numbers, each group comprising 30 patients. One group will receive maintenance ECT (M-ECT) following acute treatment of bilateral ECT of six sessions along with ongoing antipsychotic and the other group will be treated with Clozapine monotherapy. PANSS, GAF, CGI, MoCA will be re-administered at 6 weeks, 3 months, and 6 months follow-up visits to compare the changes within each group and between the groups. Post-treatment SPECT-CT of the brain will be done at the end of 6 months to document changes in the regional cerebral blood perfusion.

Clozapine monotherapy. Clozapine will be given in accordance with Maudsley guideline: 12.5 mg on the first day, followed by 12.5mg twice daily on the second day, followed by 25mg twice daily for next two days and then increment of 25mg every two days till the target dose of 250-400 mg per day in two divided doses as per tolerability of the patients

Following acute treatment with bilateral ECT of 6 sessions over a period of two weeks, Bilateral M-ECT will be administered at a frequency of 1 session/week for one month, then 1 session / 2 weeks for 2 months and then 1 session/month for next 3 months.

Clozapine will be given in accordance with Maudsley guideline: 12.5 mg on the first day, followed by 12.5mg twice daily on the second day, followed by 25mg twice daily for next two days and then increment of 25mg every two days till the target dose of 250-400 mg per day in two divided doses as per tolerability of the patients

Severity will be assessed by Positive and Negative Symptom Scale (PANSS) PANSS Score ranges from 30- 210. A higher score represents more severe psychopathology

Inclusion Criteria: Patients clinically diagnosed with treatment-resistant schizophrenia (TRS) (TRRIP consensus criteria). Patients aged 18-60 years of either sex. Patients giving voluntary written consent for participation in the study Exclusion Criteria: Patient already on Clozapine or ECT. History of psychoactive substance abuse or dependence. Co-morbid psychiatric, major medical, or neurological disorders. History of organicity or significant head injury. Pacemaker or metal in any part of the body excluding the mouth. Pregnant and breastfeeding females.

Kane JM. Management strategies for the treatment of schizophrenia. J Clin Psychiatry. 1999;60 Suppl 12:13-7.

Lieberman JA. Maximizing clozapine therapy: managing side effects. J Clin Psychiatry. 1998;59 Suppl 3:38-43.

Kim HS, Kim SH, Lee NY, Youn T, Lee JH, Chung S, Kim YS, Chung IW. Effectiveness of Electroconvulsive Therapy Augmentation on Clozapine-Resistant Schizophrenia. Psychiatry Investig. 2017 Jan;14(1):58-62. doi: 10.4306/pi.2017.14.1.58. Epub 2016 Dec 29.

Rey JM, Walter G. Half a century of ECT use in young people. Am J Psychiatry. 1997 May;154(5):595-602. doi: 10.1176/ajp.154.5.595.

Chanpattana W, Andrade C. ECT for treatment-resistant schizophrenia: a response from the far East to the UK. NICE report. J ECT. 2006 Mar;22(1):4-12. doi: 10.1097/00124509-200603000-00002.

Chanpattana W, Chakrabhand ML, Sackeim HA, Kitaroonchai W, Kongsakon R, Techakasem P, Buppanharun W, Tuntirungsee Y, Kirdcharoen N. Continuation ECT in treatment-resistant schizophrenia: a controlled study. J ECT. 1999 Sep;15(3):178-92.

Shimizu E, Imai M, Fujisaki M, Shinoda N, Handa S, Watanabe H, Nakazato M, Hashimoto K, Iyo M. Maintenance electroconvulsive therapy (ECT) for treatment-resistant disorganized schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Mar 30;31(2):571-3. doi: 10.1016/j.pnpbp.2006.11.014. Epub 2006 Dec 20.

Grover S, Hazari N, Kate N. Combined use of clozapine and ECT: a review. Acta Neuropsychiatr. 2015 Jun;27(3):131-42. doi: 10.1017/neu.2015.8. Epub 2015 Feb 20.

Petrides G, Malur C, Braga RJ, Bailine SH, Schooler NR, Malhotra AK, Kane JM, Sanghani S, Goldberg TE, John M, Mendelowitz A. Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: a prospective, randomized study. Am J Psychiatry. 2015 Jan;172(1):52-8. doi: 10.1176/appi.ajp.2014.13060787. Epub 2014 Oct 31.

Lally J, Tully J, Robertson D, Stubbs B, Gaughran F, MacCabe JH. Augmentation of clozapine with electroconvulsive therapy in treatment resistant schizophrenia: A systematic review and meta-analysis. Schizophr Res. 2016 Mar;171(1-3):215-24. doi: 10.1016/j.schres.2016.01.024. Epub 2016 Jan 27.

Siskind DJ, Lee M, Ravindran A, Zhang Q, Ma E, Motamarri B, Kisely S. Augmentation strategies for clozapine refractory schizophrenia: A systematic review and meta-analysis. Aust N Z J Psychiatry. 2018 Aug;52(8):751-767. doi: 10.1177/0004867418772351. Epub 2018 May 6.

Santra A, Kumar R. Brain perfusion single photon emission computed tomography in major psychiatric disorders: From basics to clinical practice. Indian J Nucl Med. 2014 Oct;29(4):210-21. doi: 10.4103/0972-3919.142622.

Ertugrul A, Volkan-Salanci B, Basar K, Karli Oguz K, Demir B, Ergun EL, Senturk S, Erbas B, Cila A, Ulug B. The effect of clozapine on regional cerebral blood flow and brain metabolite ratios in schizophrenia: relationship with treatment response. Psychiatry Res. 2009 Nov 30;174(2):121-9. doi: 10.1016/j.pscychresns.2009.04.007. Epub 2009 Oct 17.

Novak B, Milcinski M, Grmek M, Kocmur M. Early effects of treatment on regional cerebral blood flow in first episode schizophrenia patients evaluated with 99Tc-ECD-SPECT. Neuro Endocrinol Lett. 2005 Dec;26(6):685-9.

Sharafi M. Comparison of Classical and Clozapine Treatment on Schizophrenia Using Positive and Negative Syndrome Scale of Schizophrenia (PANSS) and SPECT Imaging. Int J Med Sci. 2005;2(2):79-86. doi: 10.7150/ijms.2.79. Epub 2005 May 10.

Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJ, Birnbaum ML, Bloomfield MA, Bressan RA, Buchanan RW, Carpenter WT, Castle DJ, Citrome L, Daskalakis ZJ, Davidson M, Drake RJ, Dursun S, Ebdrup BH, Elkis H, Falkai P, Fleischacker WW, Gadelha A, Gaughran F, Glenthoj BY, Graff-Guerrero A, Hallak JE, Honer WG, Kennedy J, Kinon BJ, Lawrie SM, Lee J, Leweke FM, MacCabe JH, McNabb CB, Meltzer H, Moller HJ, Nakajima S, Pantelis C, Reis Marques T, Remington G, Rossell SL, Russell BR, Siu CO, Suzuki T, Sommer IE, Taylor D, Thomas N, Ucok A, Umbricht D, Walters JT, Kane J, Correll CU. Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology. Am J Psychiatry. 2017 Mar 1;174(3):216-229. doi: 10.1176/appi.ajp.2016.16050503. Epub 2016 Dec 6.

Mishra BR, Agrawal K, Biswas T, Mohapatra D, Nath S, Maiti R. Comparison of Acute Followed by Maintenance ECT vs Clozapine on Psychopathology and Regional Cerebral Blood Flow in Treatment-Resistant Schizophrenia: A Randomized Controlled Trial. Schizophr Bull. 2022 Jun 21;48(4):814-825. doi: 10.1093/schbul/sbac027.