This study is designed to examine SV2A density in MDD and PTSD as a correlate of synaptic density, and to determine whether ketamine administration will reverse the synaptic loss in vivo in human subjects. To our knowledge, this is the first human study to examine SV2A in vivo in MDD and PTSD and to use the first known drug (ketamine) that rapidly reverses synaptic loss to determine whether ketamine administration could restore some of the structural changes associated with depression and PTSD.

After a screening process to determine eligibility, all subjects will participate in an MRI, and 2-3 PET scans with the administration of ketamine for one of the scans. Cognitive testing and a stress test may also be done on scan days.

The goal of the study is to determine whether there are alterations in synaptic vesicle glycoprotein 2A (SV2A), a protein expressed ubiquitously in synaptic vesicles, in depression and anxiety and whether ketamine, an N-Methyl-D-aspartate (NMDA) antagonist, normalizes SV2A density at time of its greatest anti-depressant response. This study will conduct an examination of SV2A and associated consequences using neuroreceptor imaging and behavioral techniques for the following aims.

Aim 1: To compare SV2A availability in individuals with MDD, healthy control individuals, bipolar individuals, and individuals with PTSD using APP311 or SDM-8 (aka SynVesT-1) and PET.

Hypothesis 1: This study hypothesizes lower SV2A density in MDD, BD, and PTSD in the prefrontal cortex.

Aim 2: To determine whether ketamine administration alters SV2A density in HC, MDD, and PTSD individuals.

Hypothesis 2: This study hypothesizes administration of ketamine will lead to a significant increase in SV2A density in all subject groups (HC, MDD, and PTSD), and this increase will correlate with antidepressant response in individuals with MDD.

Aim 3: To determine the extent of SV2A density changes after prolonged treatment with ketamine in individuals with depression (n=10).

Hypothesis 3: We hypothesize ketamine treatment will increase SV2A density in these individuals. These are individuals who are undergoing ketamine treatment at Yale, CMHC, or surrounding clinics.

Aim 4: To examine changes in SV2A associated with gender within each psychiatric group.

Inclusion Criteria:

• General inclusion criteria:

  1. Subjects will be 18-70 years old,
  2. English speaking,
  3. No other DSM-5 diagnosis present, besides required as below.

Inclusion criteria for depressed subjects:

1. Meet DSM-5 diagnostic criteria for Major Depressive Disorder, and for a current depressive episode.
2. Treatment or non-treatment seeking who understand that this study is for research purposes only.

Inclusion criteria for healthy controls:

1. No current, or history of any DSM-5 diagnosis.

Inclusion criteria for PTSD subjects:

1. Current Post Traumatic Stress Disorder.

Inclusion criteria for bipolar subjects:

1. Meet DSM-5 diagnostic criteria for bipolar disorder.

Inclusion criteria for subjects undergoing ketamine treatment

1. Meet DSM-5 diagnostic criteria for Major Depressive Disorder, and for a current depressive episode, as assessed by structured interview for DSM-5 diagnosis (SCID).
2. Undergoing ketamine treatment.

Exclusion Criteria:

1. History of significant medical illness that would contraindicate study participation based on above criteria and PI/MD history review.
2. Lifetime history of neurologic abnormality including seizure disorder, cerebrovascular or neoplastic lesion, neurodegenerative disorder, or significant head trauma resulting in post-traumatic amnesia >24 hours.
3. Full scale IQ lower than 70.
4. Contraindication to MRI scanning including claustrophobia and presence of a ferromagnetic object, including orthodontic braces. All participants will be screened for metal objects by the same methods used for routine clinical MRI scanning.
5. Pregnancy or breast-feeding.
6. Met DSM-5 criteria for mild substance use disorder (except nicotine and marijuana) within the past 6 months or met DSM-5 criteria for moderate to severe substance use disorder within the past year.
7. Claustrophobia.
8. Current psychosis, active suicidal or homicidal ideation.
9. Positive urine toxicology screen (except for marijuana).
10. Contraindications to PET (e.g., past or current diagnosis of cancer, poor venous access for placement of venous lines).
11. History of prior radiation exposure for research purposes within the past year such that participation in this study would place them over FDA limits for annual radiation exposure.
12. Previous or anticipated radiation exposure at work within one year of the proposed research PET scans that precludes study participation.
13. Blood pressure >130/80 (for Aim 2, ketamine challenge); blood pressure >140/90 (non-ketamine groups).
14. Arterial line exclusion: History of a bleeding disorder or currently taking anticoagulants (such as Coumadin, Heparin, Pradaxa, Xarelto).
15. Arterial line exclusion: Blood donation within eight weeks of the start of the study.
16. Current diagnosis of MDD or PTSD with psychotic features.
17. Hematocrit levels below 35 mg/dl, and/or hemoglobin levels below 10 mg/dl.
18. Weight under 110 lbs for subjects who will participate in portions of this study for which the blood draw is at or above a typical blood donation.