1. Indriani Wang, Pharm.D.-PGY1 University of Southern California (USC) USC University Hospital, Los Angeles, CA

2.  Contemporary guidelines for ECT specify a seizure duration of at least 25 seconds 1,2 and an average of 9-12 total administrations 2 to ensure adequate treatment of depression  However, many anesthesia agents used in ECT have anticonvulsant properties and suppress the generation of seizure  Moreover, individual seizure threshold varies which makes it more difficult for some patients to experience seizures of adequate duration. The following factors can increase seizure threshold 3 :  Age  Skull bone thickness  Bilateral stimulation  Repeated ECT  Drugs (benzodiazepines, barbiturates) 1.Fredman CP, et al. ECT Handbook 1995 2.American Psychiatric Association Task Force on ECT. Washington DC: APA 2001 3.Wagner KJ et al. CNS Drugs 2005;19(9):745-758

3.  Methohexital has been the standard anesthesia used for ECT but may not always be available from various suppliers  Propofol is more readily available and already used for other multiple indications within the hospital (e.g. used for sedation in ICU settings)  However, propofol has been shown in studies to produce seizures of shorter duration in comparison to methohexital 1,2,3,4  The duration of seizures, as measured clinically, was reduced with propofol (17.9 + 2.5s) in comparison with methohexital (30.9s +2.8s) (p<0.001) in fifteen patients studied during the course of six ECT administrations 1  Its place as an anesthesia agent in ECT is still yet to be determined 1.Rampton AJ et al. Anesthesiology 1989; 70:412-417 2.Malsch E et al. Convulsive Therapy 1994; 10(3):212-219 3.Fredman B et al. Anesth Analog 1994;79:75-79 4.Simpson KH et al. Br J Anaesth 1987;59:1323-1324

4. Question 1: Will maximum machine settings be reached faster with propofol? (ECT devices are regulated by the FDA and are limited to 576 mC) Question 2: Will the use of propofol require more seizure augmenting interventions during ECT compared to methohexital? General Question: Will propofol pose greater barriers in achieving a seizure of adequate duration (> 25 seconds)?

5.  Retrospective chart review of all depressed patients (n=84) meeting DSM- IV criteria for recurrent unipolar or bipolar depression from March 1999 to September 2008 treated with ECT (776 total treatments)  Patients received at least six consecutive bilateral ECT via empirical stimulus titration method InclusionExclusion All charts meeting DSM-IV criteria for recurrent unipolar or bipolar depression Charts of patients with other diagnosis (e.g. schizophrenia, bipolar mania) Patients receiving at least six consecutive bilateral ECT Patients who received less than six treatments

6. Question 1: Will maximum machine settings be reached faster with propofol? (ECT devices are regulated by the FDA and are limited to 576 mC) Question 2: Will the use of propofol require more seizure augmenting interventions during ECT compared to methohexital? 1.Number of patients who reached maximum machine settings during the first six treatments 2. Cumulative total ECT charge (in mC) exposure across all treatments (measured as Area Under the Curve- AUC) 1.Number of patients who require caffeine (seizure augmenting agent) 2. Number of patients who require anesthesia dose lowering due to short or missed seizure 3. Number of patients who require ECT re-stimulation due to short or missed seizure

7.  Baseline characteristics:  Independent samples two-tailed t-tests  Chi-square  Question #1:  Patients who reached maximum machine settings during the first six treatments (Chi-Square)  Cumulative total ECT charge measured across treatments (Wilcoxon-Mann-Whitney test)  Question #2 (Chi-Square):  Patients who used seizure lowering agent (caffeine)  Patients who needed re-stimulation with higher ECT stimulus charge  Patients who needed their anesthesia dose lowered  Statistical significance defined at p<0.05

8. PropofolMethohexitalP-value Number of patients (N=84) 4044--- Male Gender Number (%) 17 (42.5%)23(52.27%)0.3704 African American Race Number (%) 1 (2.5%)1 (2.27%)1.0000 Mean Age ±SD, years53.2 + 1554.9 + 15.30.7258 Average Weight, lbs (mean±SD) 175.9 + 44.3171.4 + 46.90.5971 Primary Diagnosis Number (%) MDD Bipolar Depressed 32 (80%) 8 (20%) 39 (88.6%) 5 (11.4%) 0.3683

9. Propofol (N=40)Methohexital (N=44)P-value Number of patients who reached maximum settings during first 6 treatments Number (%) 21 (52.5%)10 (22.7%)0.0047

10. Total Treatments Total Charge (mC) N=40, 44 *Not significant at P<.05

11. Propofol (N=40)Methohexital (N=44)P-value Number of treatments (Range) 9.5 + 2.3 (6-13) 9.0 + 2.7 (6-16) 0.2303 Range of total charge in millicoulombs (mC) 112-57664-576--- Patients who needed to use caffeine Number (%) 14 (35%) 2 (4.5%)0.0005 Patients re-stimulated at higher stimulus charge Number (%) 26 (65%)24 (54.6%)0.3296 Patients who needed lowering of anesthesia Dose- Number (%) 34 (85%)16 (36%)<0.0001

12.  This study supports current literature stating propofol use in ECT results in shorter seizure duration as demonstrated by:  Significantly higher administration of seizure augmenting interventions among patients using propofol versus methohexital  Greater number of patients who reached maximum machine settings during the first six treatments in the propofol group  Higher total stimulus charge is cumulatively needed for seizure induction with propofol

13.  Data supports propofol having anticonvulsant effects which have clinical implications for ECT clinicians who are aiming for at least 25 seconds of seizure duration  However, some proponents for propofol use in ECT argue:  Seizure quality measures (Postictal Suppression Index and Mean Integrated Amplitude) may be superior with propofol and efficacy of ECT is proven equal between the two anesthetic agents despite lower seizure duration with propofol 1  Side effects profile of propofol is better in comparison to methohexital (better hemodynamic stability, less nausea, and earlier return of cognitive function after ECT) 2  Potential future studies: prospective clinical outcome study to compare efficacy and side effect profile of each drug 1.Geretsegger C et al. J of ECT 2007; 23(4):239-243 2.Fredman B et al. Anesth Analog 1994;79:75-79

14.  Not a prospective, randomized, controlled study  However, selection bias was minimized as demonstrated by similar patient demographics  ECT administered by the same anesthesiologist and psychiatrist for a large majority of treatments  Did not assess clinical outcomes  Efficacy of ECT using propofol versus methohexital as anesthesia  Side effect profile of propofol versus methohexital

15.  Erin D. Knox, Pharm.D  Mimi Lou, MS  Kathleen A. Johnson, Pharm.D, M.P.H,Ph.D.  Tien Ng, Pharm.D, BCPS  Julie Dopheide, Pharm.D, BCPP  Carlos Figueroa, MD  Anoush Afrasiabi, MD  Chris Linton, RN

16. Augmentation StrategiesProblem(s) Addition of caffeine or theophylline-have not been demonstrated to directly improve treatment outcome -cannot use in certain population of patients (e.g. hypertensive) Re-stimulation at higher stimulus intensity of ECT -higher stimulus charge may be associated with greater side effects -May reach maximum settings sooner Lowering the dose of anesthetic agent -often accompanied by re- stimulation

17. PROPOFOLMETHOHEXITAL ClassAnesthesiaOxybarbiturate OnsetFew secondsFew minutes T1/21-8 minutes (shortest half-life among all hypnotic agents) 5-9 minutes Place in Therapy Have been demonstrated to show improved hemodynamic stability, earlier return of cognitive function after ECT, less nausea & vomiting (1) Considered gold standard of pre- ECT anesthetic agent for over 40 years by the American Psychiatric Association (APA)

18. AgentDose Succinylcholine~1 mg/kg Propofol or Methohexital Range: 1-2 mg/kg Range: 0.75-1 mg/kg As Needed Medications: BenzodiazepinesDiazepam 5-10 mg Lorazepam 2mg Midazolam 1-5 mg Lidocaine0.5- 1 mg/kg Anti-nausea agentsMetoclopramide 10 mg Ondansetron Blood pressure medicationHydralazine Caffeine200-600 mg

19. PropofolMethohexital 20 mL- $1.64 100 mL- $7.74 50mL (500mg)- $35.60 20mL (2.5 gm)- $150.47

20. PropofolMethohexitalP-value Use at least one time bzd (total: 59) 31 (77.5%)28(63.6%)0.1651 Use of high, medium, and low dose bzd Med &High 1 (3.2%) Low only 30 (96.7%) Med & High 15 (53.6%) Low only 13 (46.43%) <0.0001 Low dose benzodiazepines: midazolam 1-4mg, lorazepam 1-2mg Medium dose: midazolam 5mg, diazepam 5mg High dose: diazepam 10mg