Sleep/Wake Cycle and Depression: An Imaging and Treatment Study

The study involves four overnight stays, three occurring consecutively and one occurring at a separate timepoint. For the three-night consecutive stay, on Overnight-1, sleep can occur as normal and the investigators will measure hormone levels during sleep. On Overnight-2, participants will be kept awake for around 36 hours. On Overnight-3, the investigators will measure hormone levels again during sleep. During a separately scheduled single overnight session (which happens sometime before or after the three-night consecutive stay), three sets of imaging over the course of the night are performed. The imaging is positron emission tomography (PET). It is designed to look at brain chemistry (particularly glutamate receptors in the brain). Participants may sleep in between scans. All participants with depression enrolled in the study will be seen by a clinician throughout the study and offered medication at no cost after the study. Aim 1: Assess circadian (sleep/wake) phase in depressed and non-depressed individuals. Melatonin secretion is now an easily accessible circadian marker. Further, the average time interval between dim light melatonin onset (DLMO, the time at which melatonin rises above a certain threshold, "the most accurate biomarker of circadian phase position") and sleep midpoint (average bedtime plus half the average sleep duration) has been established as 6 hours in non-depressed participants and likely deviates from this optimum in major depressive disorder (MDD). For this reason, the investigators will measure melatonin in the blood on overnight visit 1. Hypothesis 1. Average phase angle difference (DLMO - sleep midpoint) will be 6 hours (optimal) in healthy controls, but not depressed, participants. Hypothesis 2. MDD severity (assessed by the Hamilton Depression Rating Scale, HDRS) will be correlated with deviation from optimal phase angle difference. Aim 2: Assess brain chemistry (specifically one of the glutamate receptors, the metabotropic glutamate receptor subtype 5, mGluR5) expression at 3 times: the time of DLMO, peak and nadir of melatonin secretion (as measured from overnight visit 1). mGluR5 availability will be assessed near these times to capture mGluR5 circadian rhythmicity using PET and a tracer specific for mGluR5, \[11C\]ABP688. Hypothesis 3. mGluR5 variation will be inverse to that of melatonin in both cohorts. Aim 3: Determine the effect of acute sleep deprivation on circadian rhythms. Within approximately one week of Aims 1 \& 2, all participants will receive sleep deprivation therapy. Following up to 36 hours of wakefulness (shown to increase mGluR5 at a single time point), the investigators will measure acute effects with repeat assessments of melatonin and depression severity. This will thus require two overnight stays in a row- one for the sleep deprivation and then the next to measure melatonin again in the blood while the participant sleeps. Hypothesis 4. Sleep deprivation will be most successful in the depressed participants with greatest disruption in phase (Aim 1). Hypothesis 5: Depressed participants will experience greater changes in phase angle difference following sleep deprivation than non-depressed participants. Aim 4: To determine whether reliable estimates of \[11C\]ABP688 in plasma can be obtained using a miniPET scanner. \[11C\]ABP688 concentration will be measured at the wrist or leg with a novel synchronized PET scanner developed by Stony Brook Investigator, Dr. Paul Vaska. This innovative device provides estimates of plasma radioactivity simply by placing the participant's wrist or leg in a mini-PET scanner called versaPET. The radioactivity derived from this wrist or leg scanner, as well as the resulting outcome measures, will be compared to those estimated using blood analysis. This could make future PET studies easier by finding a substitute for blood sampling during the PET scan. Uncovering the link between mGluR5, circadian disruption and MDD could: (1) Identify biological underpinnings of circadian (sleep/wake) dysfunction; (2) Identify individuals (those with mGluR5 disruption) for whom treatments like sleep deprivation would be most effective; and (3) Increase use of this safe and rapid treatment.