Ketamine as an Augmentation Strategy for Electroconvulsive Therapy (ECT) in Depression

Condition(s) targeted: Unipolar Depression; Bipolar Depression

Intervention: Ketamine (Drug); Methohexital (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: North Shore Long Island Jewish Health System

Official(s) and/or principal investigator(s):
Georgios Petrides, M.D., Principal Investigator, Affiliation: The Zucker Hillside Hospital

Overall contact:
Styliani Kaliora, M.D., Phone: (718) 470-8000, Ext: 8578, Email: skaliora@nshs.edu

The study aims to compare outcomes of Electroconvulsive Therapy (ECT) using ketamine versus methohexital anesthesia in depressed patients. The investigators hypothesize that patients who receive ketamine anesthesia during ECT will achieve remission status faster than those receiving methohexital anesthesia. Also, at the end of the ECT course subjects will display fewer cognitive side effects compared to those treated with methohexital anesthesia.

Official title: Comparing Therapeutic Efficacy and Cognitive Side Effects of Electroconvulsive Therapy (ECT) Using Ketamine Versus Methohexital Anesthesia

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Time to achieve remission

Secondary outcome: Cognitive side effects of ECT

Detailed description: Despite major advances in the treatment of mood disorders, depression remains a serious public health problem. Delayed onset of response and lack of efficacy in a significant portion of patients are the limitations of pharmacotherapy. Electroconvulsive therapy (ECT) has been shown to provide fast amelioration of depressive symptoms and its efficacy is reported to be 65 to 85%. However, one of the main limiting factors for its use is the cognitive impairment, which is directly related to the number of ECT sessions. There is increased evidence for the mediation of glutamate in the pathophysiology of depression, as suggested by the potential antidepressant effect of drugs that modulate glutamate transmission. Open studies and recent case reports demonstrate a rapid

antidepressant effect of intravenous ketamine - a non-competitive antagonist at the

glutamate N-methyl-D-aspartate (NMDA) receptor. Ketamine is a general anesthetic used commonly for procedural sedation. Ketamine has no anticonvulsant properties. It is used as

an alternative to methohexital - a barbiturate with anticonvulsant properties - in patients

with high seizure threshold. A recent open non-randomized trial by Okamoto shows a faster response when ECT is given with ketamine anesthesia. In a recent review Gregory-Roberts et al suggest that available evidence in animals and humans supports the prediction that

ketamine could effectively prevent ECT - induced persistent retrograde amnesia and improve or

hasten therapeutic response. We propose a double-blind randomized controlled pilot study to measure both therapeutic

efficacy and cognitive side effects of ECT using ketamine compared to methohexital - the

gold standard anesthetic in ECT - in depressed patients.

Thirty patients who are scheduled to receive an acute course of ECT for major depressive episode. Inpatients and outpatients will be screened by the ECT psychiatrists who participate in this study. Patients who are able and willing to provide written informed consent will be randomly assigned on a 1: 1 ratio to receive either a course of bifrontal ECT using ketamine 1-2 mg/kg or methohexital anesthesia0. 5-1. 0 mg/kg. Subjects will receive a standard acute course of ECT (3X/week. Raters and subjects will be masked to group assignment. Parallel with these procedures we will also collect magnetic resonance imaging (MRI) data on these subjects. The timeline of neuroimaging and it relation to ECT is a baseline MRI prior to first ECT, and then a follow up MRI after the first ECT (< 36hrs after), and a final MRI after 9 ECTs or if patient remits. All subjects will receive structural (i. e. diffusion tensor imaging and spectroscopy) and functional MRI exams. In addition to the imaging procedures detailed above, we also plan to acquire imaging data on healthy individuals with similar timeline. Healthy volunteers will be scanned three times; the first and second scans will be 24-48 hours apart, while the second and third scans will be two weeks apart. The imaging sessions will follow the same protocol as in the patients. The collection of control data is necessary in order to demonstrate that imaging findings are not due to acclimatization to scanner environment or other confounding sources. Compensation for participating in the MRI component is $75 per MRI.

Minimum age: 18 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Male or female subjects 18 to 70 years of age 2. Diagnostic Statistical Manual (DSM) IV diagnosis of Major Depression (296. 3), unipolar without psychotic features or Bipolar I or Bipolar II Depression without psychotic features confirmed by Structured Clinical Interview for DSM-IV (SCID-IV) interview 3. Pretreatment 24-item Hamilton Rating Scale for Depression score > 21 4. Subjects must have an initial score of at least 20 on the Montgomery-Åsberg Depression Rating Scale (MADRS) at screen 5. ECT is clinically indicated 6. Patient is competent to provide informed consent Exclusion Criteria: 1. Lifetime DSM-IV diagnosis of schizophrenia, schizoaffective disorder, psychotic depression or any other psychotic disorder as defined in the DSM-IV 2. Current (within the last year) diagnosis of anxiety disorder, obsessive- compulsive disorder, or eating disorder that precedes the onset of the current episode of depression 3. Current diagnosis of delirium, dementia, or amnestic amnesiac disorder 4. Diagnosis of Mental Retardation 5. Baseline Mini Mental State Exam (MMSE) score < 21 or a total score falling two standard deviations below the age- and education-adjusted mean, whichever is less 6. Any active general medical condition or central nervous system (CNS) disease which can affect cognition or response to treatment 7. Current (within the past three months) diagnosis of active substance dependence, or active substance abuse within the past week 8. Lifetime history of ketamine or phencyclidine (PCP) abuse or dependence 9. ECT within three months 10. The presence of any known or suspected contraindication to methohexital or ketamine including but not limited to known allergic reactions to these agents, uncontrolled hypertension, arrhythmia, severe coronary artery disease and porphyria 11. Pregnancy 12. Status 4 or greater according to the criteria of the American Society of Anesthesiologists 13. MRI contraindications

Styliani Kaliora, M.D., Phone: (718) 470-8000, Ext: 8578, Email: skaliora@nshs.edu

Zucker Hillside Hospital, Glen Oaks, New York 11004, United States; Recruiting
Styliani Kaliora, M.D., Phone: 718-470-8578, Email: skaliora@nshs.edu
Sherif N Abdelmessih, Phone: 718-470-8165, Email: sabdelme@nshs.edu
Styliani Kaliora, M.D., Sub-Investigator
Miklos Argyelan, M.D., Sub-Investigator
Ignat Bashkirov, M.D., Sub-Investigator
Georgios Petrides, M.D., Principal Investigator

Related publications:

Kellner CH, Knapp RG, Petrides G, Rummans TA, Husain MM, Rasmussen K, Mueller M, Bernstein HJ, O'Connor K, Smith G, Biggs M, Bailine SH, Malur C, Yim E, McClintock S, Sampson S, Fink M. Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression: a multisite study from the Consortium for Research in Electroconvulsive Therapy (CORE). Arch Gen Psychiatry. 2006 Dec;63(12):1337-44.

Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000 Feb 15;47(4):351-4.

Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006 Aug;63(8):856-64.

Okamoto N, Nakai T, Sakamoto K, Nagafusa Y, Higuchi T, Nishikawa T. Rapid antidepressant effect of ketamine anesthesia during electroconvulsive therapy of treatment-resistant depression: comparing ketamine and propofol anesthesia. J ECT. 2010 Sep;26(3):223-7. doi: 10.1097/YCT.0b013e3181c3b0aa.

Gregory-Roberts EM, Naismith SL, Cullen KM, Hickie IB. Electroconvulsive therapy-induced persistent retrograde amnesia: could it be minimised by ketamine or other pharmacological approaches? J Affect Disord. 2010 Oct;126(1-2):39-45. doi: 10.1016/j.jad.2009.11.018. Epub 2010 Jan 8. Review.

Sanacora G, Rothman DL, Mason G, Krystal JH. Clinical studies implementing glutamate neurotransmission in mood disorders. Ann N Y Acad Sci. 2003 Nov;1003:292-308. Review.

Ostroff R, Gonzales M, Sanacora G. Antidepressant effect of ketamine during ECT. Am J Psychiatry. 2005 Jul;162(7):1385-6.

Starting date: June 2010
Last updated: July 28, 2014