Examination of Brain Serotonin Receptors in Patients With Mood Disorders
Condition: Mood Disorder; Bipolar Disorder; Depression
MeSH terms: Depression; Bipolar Disorder; Mood Disorders
Study type: Observational

Summary: 
      The purpose of this study is to evaluate the function of certain brain chemicals and
      receptors in patients with mood disorders. This study will also examine how the stress
      hormone cortisol affects brain function.

      Data suggest that serotonin 1A (5-HT1A) receptor function is abnormal in patients with mood
      disorders, such as major depressive disorder (MDD) and bipolar disorder (BP). However, these
      data are limited because they are based on small sample sizes. In this study, PET scans will
      be used to compare 5-HT1A receptor binding potential between mood disorder patients and
      healthy volunteers.

      All participants will have an initial medical and psychiatric evaluation. Depression
      severity, anxiety, negative thinking, level of functioning, intelligence, and cognitive
      functions will be measured. Urine, saliva, and blood will be collected. Women will have a
      pregnancy test and tests to determine menstrual phase and time of ovulation. Participants
      will undergo magnetic resonance imaging (MRI) and PET scans of the brain. Some participants
      will have other procedures such as a lumbar puncture. Participants with Cushing's disease
      will undergo imaging as a comparison group.
    

Detailed description: 
      Multiple lines of evidence suggest that serotonin1A (5-HT1A) receptor and serotonin
      transporter (5-HTT) function is abnormal in major depressive disorder (MDD) and that somatic
      antidepressant treatments effect changes in the function of these systems that are relevant
      to their therapeutic mechanisms. The data supporting these hypotheses have been obtained by
      assessing neuroendocrine and temperature responses to 5-HT1A agonists in MDD subjects,
      measuring 5-HT1A receptor and 5-HTT binding in brain tissue acquired post mortem from small
      samples of MDD subjects, and examining effects on 5-HT1A receptor function in rats following
      antidepressant drug (AD) administration. The recent development of highly selective 5-HT1A
      receptor and 5-HTT radioligands for positron emission tomography (PET) imaging made direct,
      noninvasive exploration of the central serotonin sites binding possible. Two studies
      conducted using one of these, [carbonyl-11C]-WAY-100635, found reduced 5-HT1A receptor
      binding potential (BP) in the mesiotemporal cortex, the raphe, and the prefrontal cortex
      (PFC). Pilot data from these studies suggested that the abnormal reduction in 5-HT1A receptor
      BP is more prominent in bipolar disorder (BD) than MDD subjects (i.e., unipolar depressives)
      who did not have bipolar relatives, and that it exists independently of mood state.

      However, these data have the limitations that the subject samples studied in these
      preliminary post mortem and PET series have been small, and that [carbonyl-11C]WAY-100635
      uptake is difficult to quantitate in PET images. Therefore, these observations require
      replication in subject samples large enough to establish main effects of diagnostic subtype
      using a 5-HT1A receptor radioligand that can be validly quantitated. A selective 5-HT1A
      receptor radioligand suitable for this purpose, [18F]FC-WAY100635 ([18F]FCWAY), has recently
      been developed at the NIH. In addition, a recently developed selective 5-HTT ligand, [11C]
      DASB provides a unique opportunity to image the 5-HTT in the same depressed sample.

      The proposed study will advance knowledge regarding the neurobiology of mood disorders by
      employing PET and [18F]FCWAY and [11C] DASB to compare 5-HT1A receptor BP between mood
      disordered and healthy control subjects in the mesiotemporal cortex, raphe, anterior
      cingulate gyrus, and left orbital cortex. The following hypotheses, based upon pilot data
      acquired using [carbonyl-11C]-WAY-100636, will be tested: 1) Depressives have reduced 5-HT1A
      receptor binding relative to healthy controls. 2) Bipolar depressives will have significantly
      greater reductions in 5-HT1A receptor binding than unipolar depressives with only unipolar
      relatives. A pilot study in which bipolar depressives are treated with lithium or divalproex
      and then re-imaged will test the third hypothesis, that 5-HT1A receptor binding will increase
      in bipolar subjects during mood stabilizer therapy.

      Finally, because central 5-HT1A receptor density is down-regulated in rodents by
      corticosterone administration and by stress-mediated corticosterone secretion, assessments of
      hypothalamic-pituitary-adrenal (HPA) axis activity (which is commonly elevated in MDD and
      BD), will be assessed to determine whether down-regulation of 5-HT1A receptors correlates
      with cortisol hypersecretion in mood disorders. Because this down-regulation may play a
      compensatory role to reduce cortisol secretion, neuroendocrine assessments of long-standing
      rather than acute hypercortisolism and of the pathophysiological diathesis to hypersecrete
      cortisol will be emphasized as providing the most sensitive correlates of reduced 5-HT1A
      receptor binding. A medical control group with Cushing's Disease will also be imaged to
      determine whether pathological elevation of glucocorticoid levels down-regulates 5-HT1A
      receptor expression in humans, as it does in rats.
    

Keywords: PET; Major Depression; MRI; Cerebral Blood Flow; Neuroendocrine; Bipolar Disorder; Serotonin1A; Mood Disorder; Major Depressive Disorder; MDD; Depression; Healthy Volunteer; HV; Normal Control