Ketamine Anesthesia Does Not Improve Depression Scores in Electroconvulsive Therapy: A Randomized Clinical Trial Charles William Carspecken, MD, MSc, MBA,* Anna Borisovskaya, MD,† Shu-Tsui Lan, PA-C, C-AA,* Katherine Heller, MD,* Jonathan Buchholz, MD,† David Ruskin, MD,† and Irene Rozet, MD* Background: Although interest in ketamine use during electro- convulsive therapy (ECT) has increased, studies have been equivocal with regard to its efficacy. The aims of this clinical trial were to evaluate ketamine’s antidepressive effects in ECT as a primary anesthetic, determine ketamine’s tolerability when compared with standard anesthesia, and determine if plasma brain-derived neurotrophic factor (BDNF) is necessary for treatment response. Materials and Methods: Adults meeting criteria for treatment- resistant depression undergoing index course ECT received either methohexital (1 to 2 mg/kg) or ketamine (1 to 2 mg/kg) anesthesia in this dual-arm double-blinded randomized clinical trial (NCT02752724). The primary outcome of this study is change in depression questionnaire scores before and after ECT. Seizure data, depression severity using self-reported and clinician-assessed ques- tionnaires, cognitive scoring, and plasma BDNF concentrations were obtained before and after completion of ECT. Results: There were no differences in seizure lengths, hemody- namics, or seizure stimuli between the ketamine (n = 23;138 ECTs) and methohexital (n = 27;159 ECTs) groups. Depression scores improved similarly after ECT in both groups. In the me- thohexital group, 15% of patients failed to achieve adequate seizures and were switched to ketamine and 26% were converted to bilateral ECT stimulus, whereas all ketamine patients ach- ieved adequate seizures and only 4% required bilateral stimulus. Plasma BDNF increased after ECT only in the ketamine group. Conclusions: Our data show that ketamine does not significantly improve depression when compared with methohexital as a sin- gle induction agent for ECT, increases serum BDNF and does not increase rates of post-ECT agitation. Ketamine use in ECT may have some benefits for some patients that are not captured through standard depression assessment questionnaires alone. Key Words: electroconvulsive therapy, treatment-resistant depression, brain-derived neurotrophic factor, ketamine (J Neurosurg Anesthesiol 2018;00:000–000) M ajor depressive disorder (MDD) is a common mental illness with significant morbidity, mortality, and public health impact. 1 About 40% to 50% of MDD patients do not respond to traditional pharmacologic treatment; such patients are described as having treat- ment-resistant depression (TRD). 2 In these treatment- resistant cases, electroconvulsive therapy (ECT) is considered the gold standard treatment. 3 However, even with symptom improvement rates of up to 90% initially following treatment, 4 the majority of patients relapse within 6 months of index course completion; hence, prolonged maintenance courses of ECT are generally indicated following the initial index courses. 5 This chal- lenge presents an opportunity for anesthesiologists to improve patient psychiatric outcomes. Subanesthetic doses of ketamine have been shown to be effective in TRD therapy, 6 relieving depression symp- toms within hours of administration 7 and persisting for up to a week following initial administration of one dose. 8 However, relapse rates of TRD after a single ketamine infusion may be as high as 70% at one month requiring repeat dosing. 9 There is uncertainty with regard to the safety of repeat subanesthetic doses of ketamine (given its abuse potential), and studies are ongoing to determine the optimal redosing intervals to prevent symptom relapse. 10 Ketamine anesthesia for ECT poses theoretical ad- vantages in treatment of TRD over either ECT or ketamine alone. 11 Unlike methohexital, propofol, or etomidate, ket- amine does not increase the seizure threshold. 12 Some reports Received for publication March 2, 2018; accepted April 23, 2018. From the Departments of *Anesthesiology and Pain Medicine; and †Psychiatry and Behavioral Sciences, VA Puget Sound Medical Center, University of Washington, Seattle, WA. This work was supported in part by a Pilot Project Award #850 from the United States Department of Veterans Affairs. The content does not represent the views of the United States Department of Veterans Affairs or the United States Government. The sponsor had no role in the design and conduct of the study; collection, management, anal- ysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for pub- lication. The authors have no conflicts of interest to disclose. Address correspondence to: Charles William Carspecken, MD, MSc, MBA, Department of Anesthesiology and Critical Care, University of Pennsylvania, Hospital of the University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104 (e-mail: charles. carspecken@uphs.upenn.edu). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website, www.jnsa. com. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/ANA.0000000000000511 CLINICAL INVESTIGATION J Neurosurg Anesthesiol  Volume 00, Number 00, ’’ 2018 www.jnsa.com | 1 Copyright r 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. This paper can be cited using the date of access and the unique DOI number which can be found in the footnotes.