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

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

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.

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.

Participants will be randomized 1:1 to either Ketamine (experimental condition) or Methohexital anesthesia (active comparator)

Participants will be randomized 1:1 to either Ketamine (experimental condition) or Methohexital anesthesia (active comparator)

The items mostly range from a score of 0-4 but there are some questions that range from a score of 0-2. The maximum total score that can be reported is 76 and the lowest score is 0. Higher values represent a worse outcome. Items are summed together to compute the total score. Remission is defined as two consecutive Hamilton Rating Scale for Depression, 24 items (HRSD-24) scores < 10, and HRSD-24 total score does not increase > 3 points on the second consecutive HRSD-24, or remains < 6 at the last two consecutive treatments. HRSD-24 scores are used to define remission.

To determine the cognitive side effects we will use the following neuropsychological battery: Mini- Mental State Examination (MMSE), Postictal Recovery of Orientation, Rey Auditory Verbal Learning Test (RAVLT) Autobiographical Memory Interview - Short Form (AMI - SF), Subjective Memory Questionnaire (SMQ), Reading subtest of the Wide Range Achievement Test, 3rd Edition (WRAT-3), The Stroop Color Word Test (SCWT) (Golden version), Trail Making Test Part A & B, Wechsler Adult Intelligence Test-Third Edition (WAIS-III), Digit Span Subtest, WAIS-III Digit Symbol, Controlled Oral Word Association Test (COWAT), N-Back test

Neuropsychological Battery: Changes from baseline to the end of the ECT course (on average 3-4 weeks)

To use resting state and task related fMRI to identify ECT related functional network changes in the brain. Using resting state fMRI before and after ECT, we will (a) identify networks modulated by ECT (defined as a decrease or increase in functional connectivity from baseline to follow up scans), and we will (b) follow up their expression in the upcoming weeks, we will (c) identify functional networks of the brain which are correlated with superior clinical ECT outcome and we will (d) identify functional networks of the brain which are correlated with side effect profiles.

Inclusion Criteria: Male or female subjects 18 to 70 years of age 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 Pretreatment 24-item Hamilton Rating Scale for Depression score > 21 Subjects must have an initial score of at least 20 on the Montgomery-Asbergers Depression Rating Scale (MADRS) at screen ECT is clinically indicated Patient is competent to provide informed consent Exclusion Criteria: Lifetime DSM-IV diagnosis of schizophrenia, schizoaffective disorder, psychotic depression or any other psychotic disorder as defined in the DSM-IV 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 Current diagnosis of delirium, dementia, or amnestic amnesiac disorder Diagnosis of Mental Retardation 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 Any active general medical condition or central nervous system (CNS) disease which can affect cognition or response to treatment Current (within the past three months) diagnosis of active substance dependence, or active substance abuse within the past week Lifetime history of ketamine or phencyclidine (PCP) abuse or dependence ECT within three months 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 Pregnancy Status 4 or greater according to the criteria of the American Society of Anesthesiologists MRI contraindications

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