Serotonin Function During Depression
Condition: Depression, Involutional; Healthy
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major
Study type: Observational

Summary: 
      Serotonin is a chemical involved in regulation of emotions, anxiety, sleep, stress hormones,
      and other body functions. The purpose of this study is to use a procedure called tryptophan
      depletion to study the function of serotonin in people with depression and in healthy
      volunteers.

      Major depressive disorder (MDD) has been associated with reduced functioning of central
      serotonergic systems. Tryptophan depletion (TD) is a procedure used to investigate the
      relationship between serotonergic function and depression. Evidence suggests that the mood
      lowering effects of TD depend upon family history and differences in genes for a specific
      protein called 5-HTTLPR. Healthy females with a particular gene for 5-HTTLPR and a family
      history of mood disorders appear to be at a greater risk for the development of depressive
      symptoms during TD. This study will use positron emission tomography (PET) scans of the brain
      to investigate the effect of variant 5-HTTLPR genotypes on response to TD. The relationship
      between 5-HTTLPR genotypes and the effect of TD on brain activity in individuals with
      different 5-HTTLPR genes will be determined. This study will also examine how the reduced
      serotonin function that occurs in MDD affects the brain's response to sensory stimulation.

      Participants in this study will be screened by telephone about their psychiatric and medical
      history, current emotional state, anxiety and sleep patterns, and family history of
      psychiatric disorders. At study entry, participants will have an interview, physical
      examination, electrocardiogram (EKG), and blood and laboratory tests. Menstruating women will
      have a pregnancy test and tests to determine menstrual phase and time of ovulation. At the
      second clinic visit, participants will undergo tests of intelligence and cognitive abilities
      and a magnetic resonance imaging (MRI) scan of the brain. Prior to Visits 3 and 4,
      participants will collect their saliva and urine. Menstruating women will have a pregnancy
      test. At Visits 3 and 4, participants will undergo TD studies and PET scanning. During one of
      these visits, participants will take capsules of an amino acid. On the other day, they will
      take lactose capsules. Throughout the study, participants will be asked about their emotional
      state, anxiety, ability to concentrate, and well being.

      ...
    

Detailed description: 
      Major depressive disorder (MDD) has been associated with abnormally reduced function of
      central serotonergic systems by various types of evidence. One instructive paradigm for
      investigating the relationship between serotonergic function and depression has involved the
      mood response to tryptophan depletion (TD), achieved by oral loading with all essential amino
      acids excepting the 5-HT precursor, tryptophan. We obtained preliminary evidence that the
      mood lowering effect of TD depends upon the genotype for a functional polymorphism in the
      promoter region of the 5-HT transporter (5-HTT), designated 5-HTTLPR, as well as upon family
      history. In healthy females the s-allele and a positive family history for mood disorders
      appeared to be additive risk factors for the development of depressive symptoms during TD.

      The current study employs quantitative PET imaging of cerebral blood flow (CBF) and glucose
      metabolism to investigate the effect of variant 5-HTTLPR genotypes on the neurophysiological
      response to TD. The current study will examine the relationship between 5-HTTLPR genotypes
      and the TD effect on PFC metabolic activity. We will determine whether under TD the reduction
      in PFC metabolism in response to TD will occur to a greater extent in subjects with the s/s
      allele, and in subjects with a single s allele plus a family history of depression. We will
      also examine whether this reduction in PFC metabolic activity is unique to subjects who
      develop depressive symptoms during TD.

      In addition, based upon evidence that 5-HT inhibits neuronal activity in the amygdala, and
      modulates transmission of emotionally-salient sensory information from the sensory cortices
      to the amygdala, we will test the hypothesis that in MDD, reduced serotonin function
      associated with TD may disinhibit the amygdala response to sensory stimulation. This
      hypothesis will be explored by assessing the physiological responses of the amygdala to
      sensory stimuli that normally activate the amygdala, namely pictures of human faces that show
      fearful or sad emotional expressions. We are particularly interested in determining whether
      the amygdala CBF response to emotional stimuli during TD will be most prominently increased
      in subjects carrying the s-allele of the 5-HTTLPR, and whether it will be unique to subjects
      who develop depressive symptoms during TD.

      Twenty-four unmedicated-remitted subjects with MDD and 24 healthy controls will be studied in
      a double-blind, placebo-controlled, randomized (according to 5-HTTLPR genotype) crossover
      study.
    

Keywords: Depression; Tryptophan Depletion; PET; Serotonin; Pathophysiology; Emotional Stimuli; GABA MRS; MDD; Healthy Volunteer; HV; Normal Control