Brain Inflammation in Major Depressive Disorder Background

OBJECTIVE:

Inflammation in the periphery and in brain may be a predisposing factor for major depressive
disorder (MDD). For example, MDD (even in the absence of medical illness) is often associated
with raised inflammatory markers, and inflammatory medical illnesses are associated with
greater rates of MDD. Moreover, patients treated with cytokines for various illnesses are at
increased risk of developing MDD.

Translocator protein 18 kDa (TSPO) is a highly expressed protein in inflammatory cells of the
brain: activated microglia and reactive astrocytes in brain. TSPO is, thereby, a potential
biomarker of neuroinflammation. This protein can be accurately quantified using positron
emission tomography (PET) and [C(11)]PBR28, a TSPO tracer synthesized in our laboratory.

The aim of this study is to assess whether subjects with MDD have increased TSPO binding in
brain as an indirect marker of neuroinflammation.

STUDY POPULATION:

This protocol will study up to 40 patients with MDD and 30 healthy volunteers. We will
recruit up to 40 MDD subjects to achieve 30 completers. The remaining 10 MMD subjects
included in the total - account for subjects who sign consent (and therefore contribute to
the accrual ceiling) but do not complete the study for a variety of reasons.

About half of the MDD subjects will be taking antidepressant medication and half will be
unmedicated.

We will exclude subjects (approximately 10% of the population) that have low affinity for
PBR28 ( non-binders ), based on a blood test or genotyping.

All healthy volunteers must not have any current serious medical condition.

DESIGN

For absolute quantification of TSPO, both MDD subjects and healthy controls will have
arterial blood sampling concurrent with PET imaging using 11C-PBR28. We will try to minimize
the recruitment of new healthy controls by relying on our historical database of healthy
controls already scanned with [C(11)]PBR28.

OUTCOME MEASURES:

To assess absolute quantitation of TSPO with 11C-PBR28, we will primarily use the
distribution volume (VT) calculated with compartmental modeling. As the primary goal, we will
compare VT values obtained in MDD subjects with those from healthy controls. As secondary
goals, we will assess 1) the effects of medication treatment in the MDD patients and 2) the
relationship between CRP levels and TSPO binding in both MDD patients and healthy subjects.

- INCLUSION CRITERIA:

For healthy volunteers

- Age 18 or older

- No serious current medical condition

- Able to give written informed consent.

- No prior diagnosis of drug or alcohol dependence.

For patients

- Age 18 or older

- Able to give written informed consent.

Subjects will have met DSM-IV criteria for recurrent MDD in a current major depressive
episode.

-No prior diagnosis of drug or alcohol dependence.

EXCLUSION CRITERIA:

For healthy volunteers

- Any current Axis I diagnosis

- Clinically significant laboratory abnormalities other than CRP.

- Subjects with autoimmune disorders

- HIV positive

- Subjects with current infections

- Recent peripheral injury

- Smoking in the last 6 months, because smoking may cause a inflammatory responses

- Risk for MRI scan, such as a pacemaker or other implanted electrical devices, brain
stimulators, some types of dental implants, aneurysm clips (metal clips on the wall of
a large artery), metallic prostheses (including metal pins and rods, heart valves, and
cochlear implants), permanent eyeliner, implanted delivery pump, or shrapnel
fragments. Welders and metal workers are also at risk for injury because of possible
small metal fragments in the eye of which they may be unaware.

- History of neurologic illness or injury with the potential to affect study data
interpretation.

- Recent exposure to radiation (i.e., PET from other research) which when combined with
this study would be above the allowable limits.

- Inability to lie flat on camera bed for at least two hours.

- Pregnancy or breast feeding.

- Able to get pregnant but does not use birth control.

- Non binder to PBR28 determined with a blood test or genotyping

- Positive urine drug screen on the day of the scan

- Subjects receiving treatment likely to impact inflammation (e.g., chronic
antinflammatory drug treatment), statins or corticosteroids

- Significant MRI abnormalities of the brain.

- History of seizures, other than in childhood and related to fever.

- A history of drug or alcohol abuse within 6 months or a history of alcohol or drug
dependence (excepting nicotine) within 3 years (DSM-IV criteria)

For patients

- Previous radiation exposure (X-rays, PET scans etc.) that, together with study
procedures, would exceed NIH RSC research limits.

- Claustrophobia to a degree that the subject would feel uncomfortable in the MRI
machine.

- Cannot lie on their back for at least two hours.

- Smoking in the last 6 months, because smoking may cause a inflammatory responses

- Brain abnormality such as a brain tumor, stroke, brain damage from head trauma or
blood vessel abnormalities, on an MRI scan.

- Risk for MRI scan, such as a pacemaker or other implanted electrical devices, brain
stimulators, some types of dental implants, aneurysm clips (metal clips on the wall of
a large artery), metallic prostheses (including metal pins and rods, heart valves, and
cochlear implants), permanent eyeliner, implanted delivery pump, or shrapnel
fragments. Welders and metal workers are also at risk for injury because of possible
small metal fragments in the eye of which they may be unaware.

- Subjects meet criteria for bipolar disorder or schizophrenia

- Current serious suicidal ideation (e.g., thoughts of attempting suicide along with the
intent or plan to attempt suicide) or recent suicidal behavior (i.e., a suicide
attempt within the past six months)

- Current psychosis

- Medical conditions or current medications that are likely to influence cerebral
function or radiotracer delivery including cardiovascular, cerebrovascular, endocrine
or neurological diseases

- A history of drug or alcohol abuse within 6 months or a history of alcohol or drug
dependence (excepting nicotine) within 3 years (DSM-IV criteria)

- Current pregnancy or breastfeeding

- Able to get pregnant but does not use birth control

- Subjects with autoimmune disorders

- Subjects with current infections

- HIV positive

- Recent peripheral injury

- Subjects receiving treatment likely to impact inflammation (e.g., chronic
antinflammatory drug treatment), statins or corticosteroids

- Subjects unable to travel independently to participate in the research study because
of the severity of their depression.

- Non binder to PBR28 determined with a blood test or genotyping

- Positive urine drug screen on the day of the scan.