Clinical Effectiveness and Cognitive Impact of Electroconvulsive Therapy for Schizophrenia: A Large Retrospective Study Tyler S. Kaster MD, Zafiris J. Daskalakis MD PhD, and Daniel M. Blumberger MD MSc Centre for Addiction and Mental Health Department of Psychiatry, University of Toronto International Society for ECT and Neuromodulation Atlanta, Georgia May 15, 2016

Disclosures No financial support for this study TSK – None DMB – Non-salary operating funds from Brainsway Ltd. – In-kind equipment support from Brainsway Ltd. and Tonika/Magventure – Site principal investigator for clinical trials from Brainsway Ltd. ZJD – Non-salary operating funds from Brainsway Ltd. – In-kind equipment support from Brainsway Ltd. – Advisory board of Hoffmann-La Roche Limited and Merck – Speaker support from Sepracor and Eli Lilly

Learning Objectives At the conclusion of this activity, the participant will be able to: 1.Describe the rate of treatment response to ECT in patients with schizophrenia 2.Identify clinical and treatment characteristics associated with response to ECT for patients with schizophrenia 3.Describe the rate of cognitive impairment from ECT in patients with schizophrenia

Introduction

Treatment Resistant Schizophrenia Clozapine is the only evidence based treatment with superior efficacy (Lehman 2004) – Difficulties with tolerability, side effects or non- compliance No evidence-based pharmacologic adjunctive or augmentation therapies for treatment-resistant schizophrenia (Taylor 2009, Sommer 2012)

Electroconvulsive Therapy (ECT) Recent Cochrane review concluded: – “ECT combined with treatment with antipsychotic drugs may be considered an option for people with schizophrenia.” (Tharyan and Adams 2005) Recent randomized control trial found a 50% response rate when ECT added to clozapine (Petrides 2015)

Limitations of Current Evidence Most studies used typical antipsychotics in conjunction with ECT (Chanpattana 1999, Chanpattana 1999, Chanpattana & Sackeim 2010) Minimal data on the use of modern ECT technology (i.e. ultra-brief pulse width) (Pisveic 1998) A variety of cognitive rating scales have been used with conflicting results (Tharyan & Adams 2005)

Study Objectives 1)Determine clinical effectiveness and cognitive impact of ECT in a clinical sample of patients with schizophrenia 2)Determine factors associated with ECT treatment response and adverse cognitive effects.

Methods

Study Design & Subjects Conducted at the Centre for Addiction and Mental Health in Toronto, Canada Retrospective chart review all patients referred to ECT treatment program between October 2009 – August 2014 (n=171) Inclusion criteria: – DSM-IV diagnosis of schizophrenia or schizoaffective disorder – At least one acute course of ECT

ECT Technique Device was MECTA spECTrum 5000Q Electrode placement determined by consultant ECT psychiatrist based on clinical factors such as: – risk of cognitive side effects need for rapid response, and previous treatment protocols – Generally BL electrode placement was selected based on literature (Kellner et al., 2010)

ECT Technique Electrode Placement Pulse width (ms)Current (mA) Bilateral (BL) Right unilateral (RUL) Right unilateral- ultrabrief (RUL-UB) 0.3 –

ECT Technique Seizure threshold – determined by stimulation titration method – stimulus intensity set at 1.5 times the seizure threshold Adequate seizure = 15 seconds of peripheral motor manifestation Anaesthetic agent: methohexital mg/kg IV Muscle relaxant: succinycholine mg/kg IV

Assessment of Treatment Response Estimated the clinical global impression improvement (CGI) from patient’s chart: 1.Excellent: dramatic benefit from ECT Treatment 2.Good: patient responded well 3.Moderate: patient received some benefit 4.Poor: patient had minimal to no benefit Response = 1 or 2 Non-response = 3 or 4

Validation of Treatment Response Subset of patients (n=89) had physician rated CGI score available Good inter-rater agreement between chart estimate of CGI and physician rated CGI (kappa=0.7597)

Assessment of Cognitive Impairment Subset of patients (n=89) had physician rated cognitive impairment on following scale: 1.None 2.Mild – no functional impairment 3.Moderate – functional impairment 4.Severe – significant functional impairment Non-significant impairment = 1 or 2 Significant impairment = 3 or 4

Assessment of Cognitive Impairment Attempted to estimate cognitive impairment from chart – 62% of charts did not reference cognitive impairment

Results

Table 1. Patient demographic and treatment features of the treatment cohort (n=171) Demographic/Clinical Age ± SD [Max-Min] (years)45 ± 14.0 [ ] Male gender (%)105 (61.4) Schizophrenia Diagnosis (%)100 (58.4) Schizoaffective Diagnosis (%)71 (41.5) Lacked capacity to consent to ECT (%)102 (59.6) Medications Oral/Depot antipsychotic (%)169 (98.8) Depot antipsychotic (%)56 (32.7) Clozapine antipsychotic (%)82 (47.9) Benzodiazepine use (%)33 (19.3) Antidepressant treatment (%)51 (29.8) Mood stabilizer/AED treatment (%)24 (14.0) Treatment Setting Inpatient (%)163 (95.3) Voluntary Inpatient (%)82 (50.2) Outpatient (%)8 (4.7)

ECT Outcome 76.7% of ECT courses resulted in treatment response

Table 2. ECT treatment details of the treatment cohort (n=171) ECT Indication Failed pharmacotherapy (%)125 (73.1) Prior good response to ECT (%)54 (31.5) Suicidality (%)28 (16.3) Failed continuation maintenance pharmacotherapy (%)26 (15.2) Violent behaviour (%)23 (13.4) Intolerance of adequate pharmacotherapy (%)20 (11.7) Patient preference (%)16 (9.3) ECT Electrode Placement BL (%)147 (86.0) BL  RUL (%) 5 (2.9) RUL (%)11 (6.4) RUL  BL (%) 8 (4.7) RUL-UB (% of RUL courses)9 (37.5) Multiple Treatment Courses Two Courses (%)23 (13.4) Three Courses (%)4 (2.3) Other Mean number of treatments ± SD [Min-Max]12.2 ± 6.5 [1 - 38] Previous ECT (%)72 (42.1) Referred for maintenance treatment (%)77 (45.0) Discharged within 31 days of treatment completion (%)73 (44.8)

Table 3. Factors associated with treatment response to ECT (n=168) Treatment Response (n=129) Non-treatment response (n=39) P-value Referral Indication Failed pharmacotherapy (%)90 (69.8)35 (89.7)0.012 Prior good response to ECT (%)47 (36.4)6 (15.4)0.017 Suicidality (%)20 (15.5)8 (20.5)0.47 Failed continuation maintenance pharmacotherapy (%) 21 (16.3)5 (12.8)0.80 Violent behaviour (%)19 (14.7)4 (10.3)0.60 Intolerance of adequate pharmacotherapy (%)14 (10.9)6 (15.4)0.41 Patient preference (%)12 (9.3)4 (10.3)1

Table 3. Factors associated with treatment response to ECT (n=168) Treatment Response (n=129) Non-treatment response (n=39) P-value Demographic/Clinical Mean age (years) Schizophrenia diagnosis (%)72 (55.8)26 (66.7)0.27 Catatonia (%)7 (5.4)3 (7.7)0.70 Medications during ECT Clozapine (%)62 (48.1)20 (51.3)0.85 Mood Stabilizer/AED (%)14 (10.9)10 (25.6)0.034 AED (%)5 (3.9)7 (17.9)0.007 Lithium (%)9 (7.0)5 (12.8)0.32 Benzodiazepine use (%)23 (17.8)9 (23.1)0.49 Benzodiazepine dose >= 2mg lorazepam equivalent (%) 8 (6.2)4 (10.3)0.48

Table 3. Factors associated with treatment response to ECT (n=168) Treatment Response (n=129) Non-treatment response (n=39) P-value ECT Characteristics First treatment course (%)105 (81.4)36 (92.3)0.14 Mean number of treatments <=6 Treatments (%)25 (19.4)9 (23.1)0.65 BL Treatment (%)114 (88.4)39 (100)0.02

ECT Outcome 76.7% of ECT courses resulted in treatment response 9.0% of patients developed clinically significant cognitive impairment

Table 4. Factors associated with cognitive impairment after ECT (n=89) No cognitive impairment (n=81) Cognitive impairment (n=8) P-value Demographic/Clinical Mean age (years) Medications Mood Stabilizer/AED (%)10 (12.3)0 (0)0.59 AED (%)4 (4.9)0 (0)1 Lithium (%)8 (9.9)0 (0)1 Benzodiazepine use (%)15 (18.5)0 (0)0.34 Benzodiazepine dose >=2mg lorazepam equivalent (%) 7 (8.6)0 (0)1 ECT Characteristics Mean number of treatments <=6 Treatments (%)12 (14.8)0 (0)0.59 BL Treatment (%)71 (87.7)8 (100)0.59

Discussion

Factors associated with treatment response – Anti-epileptic drug treatment – Previous good response to ECT – Failed pharmacotherapy – Electrode placement Factors NOT associated with treatment response – Benzodiazepine use – Clozapine treatment

Discussion No factors associated with cognitive impairment Limited number of patients with clinically significant cognitive impairment (n=8)

Limitations Retrospective study Coarse outcome measure for CGI estimate and cognitive impairment

Future Work Prospective trials using validated scales Maintenance ECT Treatment biomarkers Optimizing ECT parameters New technologies with similar efficacy, but reduced cognitive burden

Conclusion ECT – effective for acute treatment – associated with relatively minimal cognitive impairment in patients with schizophrenia Factors associated with treatment response may aid in selecting patients for ECT Future work is required to determine factors associated with cognitive impairment

Appendix 1. Treatment response agreement (kappa = ) between clinical note CGI and clinician CGI (n=89) Clinical Note CGI 1234 Clinician CGI

Clinical Note CGIN% No records3NA Clinician CGIN%