Mechanistic Clinical Trial Evaluating the Role of the Metabotropic Glutamate Receptor Subtype 5 (mGluR5) in the Antidepressant Mechanism of Cognitive Behavioral Therapy for Insomnia (CBT-I)

More than 80% of adults with depression endorse one or more symptoms of insomnia, such as high sleep latency (difficulty falling asleep). When comorbid insomnia is not addressed, it results in worsened depression severity, a doubled probability of relapse and increased risk of suicide. Conversely, cognitive behavioral therapy for insomnia (CBT-I), a treatment solely aimed improving sleep, reduces depression with rates similar to conventional antidepressants. Although this efficacy reflects the interrelationship between sleep and depression, CBT-I’s antidepressant mechanism of action is currently unknown. One potential mechanistic pathway is through the metabotropic glutamate receptor subtype 5 (mGluR5), due to its strong association with both depression and sleep. Preclinical studies repeatedly implicate mGluR5 in the pathophysiology of depression. Correspondingly, mGluR5 antagonists and negative allosteric modulators induce a dose- dependent antidepressant effect. In humans, we and others have shown altered mGluR5 density in major depressive disorder (MDD) in vivo and postmortem. We have also shown that ketamine reduces mGluR5 density, and these reductions are correlated with its antidepressant efficacy. In terms of sleep, four different studies across rodents and humans have shown that global increases in brain mGluR5 density are induced by one night of sleep deprivation. Conversely, lower mGluR5 density in humans is correlated with less subjective sleepiness and reduced markers of sleep need. In our own pilot data in two different cohorts and using three modalities (positron emission tomography [PET], self-report surveys and polysomnography), we have found that lower mGluR5 density is significantly associated with better sleep, including lower sleep latency. Taken together, we hypothesize that a reduction in mGluR5 is the common pathway between sleep and depression improvement. We will test this hypothesis in 42 adults with MDD and a range of sleep latencies. We focus on reduction of sleep latency as a readout of improved sleep given that it is easily quantifiable, significantly improved by CBT-I, and correlated with depressive symptoms. mGluR5 density (quantified by PET) and sleep latency (quantified by polysomnography) will be assessed before and after nine weeks of a validated, online CBT-I program developed by MPI Dr. Ritterband. We hypothesize that (1) CBT-I will result in a significant reduction of mGluR5 density, (2) this reduction will be correlated with reduction in sleep latency (improved sleep) and (3) CBT-I will be most effective in those with high pretreatment mGluR5, establishing a personalized marker of treatment efficacy. In exploratory analyses, we will examine other measures of sleep and all brain regions. Upon hypothesis validation, this study would be the first to show that a lifestyle-based intervention can alter mGluR5 density. As mGluR5 has been implicated in many disorders, and medications targeting mGluR5 have generally not been viable in humans due to significant side effects, a sleep-based mechanism of altering mGluR5 would have multiple therapeutic implications beyond depression.