This study is designed to look at that involvement of a process in the brain called the glutamate system in depression. Participants will undergo a screening session, up to two functional Magnetic Resonance Imaging (fMRI) scans, and up to three Positron Emission Tomography (PET) scans, as well as cognitive testing at each scan session. For one of the PET scans, a drug (either ketamine or n-acetyl cysteine) will be administered.

Hypothesis 1: The investigators hypothesize administration of ketamine or n-acetylcysteine (NAC) will lead to a decrease in mGluR5.

Hypothesis 2: The investigators hypothesize an improvement in memory and attentional skills after drug challenge.

Hypothesis 3: The investigators hypothesize an increase in mGluR5 availability and change in MRI measures post drug challenge as compared to baseline, signifying synaptogenesis.

Hypothesis 4: We expect there should not be a significant difference in reduction in mGluR5 availability due to differences in ABP688 radiotracer infusion.

Aim 1: To determine the acute effect of medication-induced glutamate release on mGluR5 availability in human subjects. Hypothesis 1: We hypothesize administration of ketamine or n-acetylcysteine (NAC) will lead to a decrease in mGluR5 availability.

Aim 2: To determine if glutamate release via administration of ketamine or NAC has pro cognitive benefits.

Hypothesis 2: We hypothesize an improvement in memory and attentional skills after drug challenge.

Aim 3: To determine if there is synaptogenesis detectable by PET and MRI post ketamine or NAC within a week of drug challenge (at the time of greatest antidepressant response). Hypothesis 3: We hypothesize an increase in mGluR5 availability and change in MRI measures, post drug challenge as compared to baseline, signifying synaptogenesis.

Aim 4: To determine if there is a difference in reduction of mGluR5 availability after ketamine administration when radiotracer is administered bolus as compared to bolus to constant infusion in the same subjects (ABP688 radiotracer only).

Hypothesis 4: We expect there should not be a significant difference in reduction in mGluR5 availability due to differences in ABP688 radiotracer infusion.

Inclusion Criteria:

• 18-65 years old
• English speaking
• No other Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) diagnosis present, besides required as below.

Inclusion criteria for depressed subjects

• clinical diagnosis of a current or past depressive episode
• medication free for at least 2 weeks
• Score >16 on Hamilton Depression Rating Scale (HDRS) if currently depressed or <11 if not currently depressed
• treatment or non-treatment seeking who understand that this study is for research purposes only

Inclusion criteria for healthy controls

• no current, or history of, any DSM-IV diagnosis
• no first-degree relative with history of psychotic, mood, or anxiety disorder

Inclusion criteria for PTSD subjects

• current Post-Traumatic Stress Disorder, as determined by the Structured Clinical Interview for DSM-IV-Text Revision (TR) (SCID) patient research edition
• Clinician Administered PTSD Scale for DSM-IV-TR (CAPS) score of 50 or higher

Inclusion criteria for trauma control subjects

-history of trauma (meeting the criterion A of PTSD but not a full diagnosis of PTSD)

Exclusion Criteria:

• Current or past significant medical, neurological, or metabolic disorder or loss of consciousness for 5 minutes or more
• active, significant suicidal ideation
• implanted metallic devices or any Magnetic Resonance (MR) contraindications
• women who are pregnant or breastfeeding
• met DSM-IV criteria for alcohol/illicit substance dependence in their life-time or met alcohol/illicit substance abuse within past year
• 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. This guideline is an effective dose of 5 rem received per year
• blood donation within eight weeks of the start of the study
• radiation exposure at work that precludes study participation
• blood pressure >140/80

reason for discrepancy: some subjects completed baseline scan but did not continue with ketamine administration and subsequent scans.

4 years

Standard assessments and regular observations are used to determine whether or not certain adverse events have occurred.

Study lacks placebo control group Hemodynamic effects of ketamine may alter tracer delivery and washout Study lacks long-term follow up Only non-smokers studied Ketamine dose administered is higher than typical dose used for clinical purposes