PET Biomarkers in Treatment Resistant Depression

While Major Depressive Disorder (MDD) is prevalent and disabling, compelling recent data
from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study indicate that
only about half of patients attain remission from MDD, even after multiple antidepressant
medication trials. Further, no biomarker has been validated which can select an effective
treatment for such patients, presenting critical unmet intellectual and clinical challenges.
The recent landmark finding of an markedly elevated level of monoamine oxidase A (MAO-A)
in the brains of depressed patients with MDD compared to controls, using positron emission
tomography (PET) with a [11C] labeled monoamine oxidase inhibitor (MAOI), has provided an
unparalleled opportunity to address these challenges. It has long been known that MAOIs are
effective for some patients with treatment-resistant MDD, although their side effect profile
makes them highly unacceptable both to patients and physicians, severely curtailing their
utility.

This study seeks to: 1) replicate this study using PET scans in 20 subjects with MDD but
extending it to patients with treatment-resistant depression (TRD). (Results from these
participants with be compared to those from 10 non-depressed controls who have participated
in IRB #5461 "Quantifying Cerebral Monoamine Oxidase-A Enzyme Activity by PET with [11C]
methoxymethylpyridoindole: Test-retest and fMRI Correlation"); 2) explore the correlation
of the brain MAO-A level biomarker to treatment outcome by treating the 20 PET-imaged TRD
patients with an MAOI, hypothesizing that their MAOI response will be related to their level
of MAO-A. Brain MAO-A is an ideal candidate biomarker for this study since it appears to be
significantly abnormally elevated in MDD, yet it has a broad range of values even among
depressed patients. Most importantly, the MAO-A biomarker is known to be the single
pharmacologic target of the treatment, making it appear likely that outcome with MAOI
treatment will be related to MAO-A.

INCLUSION:

1. Primary diagnosis of Major Depressive Disorder

2. Subjects aged 18-65

3. Depressed subjects must have Treatment-Resistant Depression (TRD) two previous
adequate antidepressant treatment trial failures within the current depressive
episode from different classes

4. Minimum baseline MADRS score of 22

5. Signs informed consent form

6. Subjects must be willing to be have a PET scan

7. Subjects must be antidepressant medication free for 3 weeks prior to PET scan

EXCLUSION

1. Significant past or present neurological disorder, including seizures, stroke, or
head trauma

2. History of bipolar disorder, psychosis, schizoaffective disorder, or schizophrenia

3. Moderate or high level of suicide risk, as determined by a score of 3 or 4 on item 3
of the HAM-D scale. Also excluded will be those who present a significant suicide
risk by history or current psychiatrist's assessment.

4. Personality disorder which might interfere with compliance or increase suicide risk

5. Alcohol or drug abuse or dependence in the past year; history of lifetime IV drug use
or use of MDMA ("ecstasy") more than twice

6. Current thyroid dysfunction (past or currently treated dysfunction is acceptable)

7. Clinically significant or unstable medical conditions or laboratory abnormalities,
including hypertension (repeated BP > 140 systolic, > 90 diastolic)

8. Intake of investigational (unapproved) drug in the past 3 months

9. ECT in three months prior to screening

10. Use of Vagal Nerve Stimulation (VNS)

11. Positive drug of abuse screen

12. Anticoagulant treatment which cannot be discontinued for 10 days prior to PET
scanning

13. Pregnancy, currently lactating; planning to conceive during the course of study
participation or abortion in the past two months.

14. Dementia (clinical and neurocognitive criteria)

15. Claustrophobia of a severity which would not permit the participant to undergo an MRI
or a PET scan

16. Recent (< 7 days) consumption of Ayahuasca Tea or other South American non-standard
decoction.

17. Presence of metallic devices, implants and other contraindications to scanning

18. Current, past or anticipated exposure to radiation, that may include being badged for
radiation exposure in the workplace or participation in nuclear medicine research
protocols

19. Smokers (use of tobacco products in the previous 3 months)

20. Potential participants having taken an antidepressant medication in the last 3 weeks.
Participants otherwise eligible may elect to discontinue medication which has not
been significantly helpful according to their report, their current psychiatrist's
report (if available), and the evaluating DES psychiatrist. No patient will be asked
to discontinue an effective antidepressant medication to participate.

21. History of previous MAO-I treatment