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

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.

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-Asbergers
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