Imaging Serotonin 5HT1A Receptors in Patients With Major Depressive Disorder

Anxiety Disorder, Depression, Major Depression, Unipolar Depression

5-HT1A Receptors, Major Depression, PET Imaging, Depression, Healthy Volunteer, HV

Background: \- Medications to treat major depression act on a brain chemical called serotonin, which binds to receptors on brain cells. More research is needed on how serotonin receptors work in the brain, and imaging studies such as magnetic resonance imaging (MRI) can provide information on how these receptors function in the brains of individuals with depression and healthy volunteers. The experimental radioactive chemical \[11C\]CUMI has been designed to react with serotonin receptors, and researchers are interested in studying its effectiveness using positron emission tomography (PET) scanning to see how well it gets into the brain. Objectives: \- To evaluate the effectiveness of the radiotracer \[11C\]CUMI in brain imaging studies of serotonin receptors. Eligibility: \- Individuals between 18 and 55 years of age who either have been diagnosed with major depressive disorder or are healthy volunteers. Design: * Participants will be screened with a full medical history, physical and psychiatric examination, blood and urine tests, and questionnaires about mood. Participants will also have an electrocardiogram at this visit. * At the first study visit, participants will have a MRI scan of the brain to provide baseline data on brain function. * At the second study visit, participants will have a PET scan with the \[11C\]CUMI contrast agent. * No treatment will be provided as part of this protocol....

Eighteen million people in the United States are currently suffering from Major Depressive Disorder, which is characterized by episodes of low mood, poor self attitude and poor vitality. Of those suffering from Major Depressive Disorder (MDD), only one third completely improve, but even among these cases, there is a waiting period of several weeks or more during which antidepressants take effect. Our inability to adequately treat MDD is evident in its being ranked number one in Disability Adjusted Life Years (DALY) among persons aged 15-44. Given this profound burden, improving our understanding of the molecular basis of MDD is of utmost importance in the development of novel antidepressant medications. Serotoninergic neurotransmission is implicated in MDD, as demonstrated by the relative success of selective serotonin reuptake inhibitors (SSRIs). SSRIs block the reuptake of serotonin through the serotonin transporter, which then increases serotonin at the synaptic cleft. Serotonin then binds to 5-HT1A receptors, which are G-protein coupled receptors that are present both presynaptically and postsynaptically. Presynaptically, these receptors act as autoinhibitory receptors, triggering decreased firing rates and serotonin release. This autoinhibition, which lasts for about two weeks, is believed to be the reason why patients experience a delay in symptomatic improvement after initiation of SSRIs. Serotonin binding to postsynaptic receptors mediates symptomatic improvement of depression. Multiple positron emission tomography (PET) studies utilizing antagonists at 5-HT1A have been conducted. The results are mixed, with some noting increased and others noting decreased 5-HT1A in the brains of patients with MDD. While clinical heterogeneity and the effects of previous treatment with SSRIs may be confounding factors, the lack of consistent finding could also be secondary to using antagonist rather than agonist radioligands. Unlike agonists, antagonists are unable to discriminate between 5-HT1A in the high and low affinity states, and only the high affinity state, which is G-protein-coupled, allows for activity at the 5-HT1A receptor. We propose a PET study using 5-HT1A radiolabelled agonist, C(11)CUMI, to determine whether there is a difference in the density and distribution of 5-HT1A in the high affinity state in the brains of patients with MDD versus controls. We will perform an internal control at 1-5 days after initiation of SSRI to determine whether increased serotonin causes detectable displacement of C(11)CUMI. At 4-8 weeks after initiation of SSRI treatment, we will reimage patients to determine whether there is a change in the density of 5-HT1A in the high affinity state.

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