Investigating the brain's response to inflammation in major depressive disorder

Inclusion Criteria:

Both healthy controls and depressed participants will be required to be in good general health (as evaluated during Visit 1, including EKG) and to be 18-65 years of age. A DSM-V diagnosis of MDD will be made with the MINI International Neuropsychiatric Interview and current symptoms of depression will be measured with the clinician-administered MADRS and the self-report PHQ-9. Depressed participants will be required to have symptoms of depression (i.e. a PHQ-9 score ≥10) and/or a MADRS score of ≥7.

Exclusion Criteria:

General Exclusion Criteria:

* Pregnancy
* A history of fainting during blood draws will be evaluated by the clinical team and may be deemed exclusionary.

Medical Conditions:

* Moderate to severe traumatic brain injury (\>30 min. loss of consciousness or \>24 hours posttraumatic amnesia) or other neurocognitive disorder with evidence of neurological deficits.
* Presence of co-morbid medical conditions not limited to but including cardiovascular (e.g., history of acute coronary event, stroke) and neurological diseases (e.g., Parkinson's disease), as well as pain disorders.
* Presence of co-morbid inflammatory disorders such as rheumatoid arthritis or other autoimmune disorders.
* Presence of an uncontrolled medical condition that is deemed by the investigators to interfere with the proposed study procedures, or to put the study participant at undue risk.
* Presence of chronic infection that may elevate pro-inflammatory cytokines.
* Presence of an acute infectious illness or receipt of a vaccination in the two weeks prior to an experimental session.

Psychiatric Disorders:

* Current severe suicidal ideation or attempt within the past 12 months.
* Psychosis
* Bipolar disorder
* Substance abuse or dependence within the previous 6 months

Contraindications for MRI:

* Cardiac pacemaker, metal fragments in eyes/skin/body (shrapnel), aortic/aneurysm clips, prosthesis, by-pass surgery/coronary artery clips, hearing aid, heart valve replacement, shunt (ventricular or spinal), electrodes, metal plates/pins/screws/wires, or neuro/bio-stimulators (TENS unit), persons who have ever been a professional metal worker/welder, history of eye surgery/eyes washed out because of metal, vision problems uncorrectable with lenses, inability to lie still on one's back for 60 minutes; prior neurosurgery; tattoos or cosmetic makeup with metal dyes, unwillingness to remove body piercings, and pregnancy.
* Claustrophobia that is severe enough to preclude MRI scanning.

Medications:

* Current and/or past regular use of hormone-containing medications (excluding contraceptives)
* Use of medications such as oral corticosteroids which may have immunosuppressive effects.
* Current use of non-steroid anti-inflammatory drugs that is deemed by the investigators to potentially confound the results of the study (e.g. \> 3 days/week)
* Current and/or past regular use of immune modifying drugs that target specific immune responses such as TNF antagonists
* Current use of analgesics such as opioids or history of addiction to opioids or other analgesics
* Current and/or past regular use of cardiovascular medications, including antihypertensive, antiarrhythmic, anti-anginal, and anticoagulant drugs (does not apply where medications are taken for different purpose e.g. anti-hypertensives for migraine).
* Chronic use of antibiotics such as isotretinoin or minocycline because of their potential effects on the microbiome and immune function.
* Evidence of recreational drug use from urine test.
* Lifetime use of methamphetamine
* Inclusion of individuals reporting other types of medications or supplements not listed or considered thus far will be at the discretion of the PI based on their potential to affect immune function, the microbiome, brain function or brain blood flow.

Health Factors:

* BMI \> 35 because of the effects of obesity on pro-inflammatory cytokine activity
* Clinically significant abnormalities on screening laboratory tests
* Abnormal EKG
* In addition, participants who on arrival to the study, show any of the following symptoms will not be allowed to complete the study:

  1. screening supine systolic blood pressure \>140 mmHg or \<100 mmHg
  2. screening supine diastolic blood pressure \>90 mmHg or \<60 mmHg
  3. 12-lead EKG demonstrating a PR interval \> 0.2 msec QTc \>450 or QRS \>120 msec (Bazett) If the QTc exceeds 450 msec, or QRS exceeds 120 msec, the EKG will be repeated 2 more times and the median value will be used
  4. pulse less than 50 beats/minute or greater than 100 beats/minute
  5. temperature greater than 99.5 degrees F.

     Non-English speaking participants:
* The majority of the assessments proposed for this study have not been translated from English, thus, non-English speaking volunteers will be excluded.