Effects of Tryptophan Depletion on Brain Processing of Emotions in Patients With Mood Disorders
Condition: Depressive Disorder, Major
MeSH terms: Depressive Disorder; Depression; Mood Disorders; Depressive Disorder, Major
Study type: Observational

Summary: 
      This study will investigate how the brain process emotions in healthy people and in patients
      who have major depression in order to better understand the causes of depression. It will
      examine what happens in the brain when a person responds to words related to different
      emotions while the brain's ability to manufacture a chemical called serotonin is reduced.
      Serotonin regulates functions such as emotion, anxiety and sleep, and stress hormones such as
      cortisol. In this study, participants' serotonin levels are reduced by depleting tryptophan,
      an amino acid that is the main building block for serotonin.

      Healthy volunteers and patients with major depression that has been in remission for at least
      3 months may be eligible for this study. Candidates must be between 18 and 50 years of age
      and right-handed. They are interviewed about their medical and psychiatric history, current
      emotional state and sleep pattern, and family history of psychiatric disorders. Screening
      also includes psychiatric interviews and rating scales, neuropsychological tests, physical
      examination, electrocardiogram (EKG), and blood, urine, and saliva tests. Women have their
      menstrual phase determined by a blood test and home urine ovulation test kit.

      The study involves two clinic visits in which participants undergo tryptophan depletion and
      magnetic resonance imaging (MRI). Subjects arrive at the NIH Clinical Center in the morning
      after fasting overnight. They fill out questionnaires have a blood sample drawn, and then
      take 74 capsules that contain a mixture of amino acids found in the diet. At one visit they
      are given capsules that contain a balanced mixture of amino acids one would normally eat in a
      day; at the other visit, some of the capsules contain lactose instead of tryptophan, causing
      tryptophan depletion. At 2 p.m. participants fill out the same questionnaires they completed
      at the beginning of the day and have another blood sample drawn. Then they do a computerized
      test in the MRI scanner. MRI uses a magnet and radio waves to obtain pictures of the brain.
      For the test, subjects lie on a narrow bed that slides into the cylindrical MRI scanner. They
      are asked to press a button in response to words associated with different emotions that
      appear on a screen. Arterial spin labeling - a test that uses magnetism to measure blood flow
      in different areas of the brain-is also done during the procedure. After the scan, subjects
      eat a meal and then return home.

      DNA from the participants' blood samples is also examined to try to better understand the
      genetic causes of depression. Some of the white cells from the samples may also be grown in
      the laboratory so that additional studies can be done later.

      ...
    

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, cognition 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. Subjects who are depressed
      show altered behavioral and neural response to affectively valenced stimuli, similar to those
      seen under TD.

      More, specifically, increased response latencies to happy words have been noted in both
      depressed patients and healthy controls following TD using the Affective Go/No go (AGNG)
      test, in which subjects are required either to respond or inhibit a response to a series of
      emotionally valenced words.

      The first round of our study employed fMRI imaging of BOLD response and arterial spin
      labeling to investigate response to affectively valenced words under TD in two groups,
      remitted MDD (rMDD) patients and healthy controls with no family history of depression. We
      have thus far examined the effects of TD depletion in our healthy control group. We found
      that emotional information processing was indeed altered by 5-HT depletion.

      A behavioral bias toward positive stimuli was attenuated following depletion, which was
      accompanied by increased hemodynamic responses during the processing of emotional words in
      several subcortical structures, including the ventral striatum, hippocampal cortex, anterior
      insula, superior temporal gyrus and posterior cingulate. Further, inter-individual
      differences in tryptophan depletion-elicited anxiety correlated positively with caudate bias
      toward negative stimuli. On the basis of these data, we suggest that the bias towards
      positive stimuli might represent a normal suppression of attention to negative stimuli; a
      process which is abrogated in conditions, such as depression, which are characterized by a
      serotonergic dysfunction. In the second round of this study, we are examining whether such
      biases also occur beneath the level of conscious awareness.

      One of the weaknesses of these data is that the patients were consciously aware of the verbal
      stimuli that were presented to them and likely possess learned, individualized associations
      to the verbal stimuli in question. We have developed a conditioning task which obviates this
      problem through the presentation of emotionally-valenced visual stimuli below the threshold
      of conscious awareness.

      Since embarking on the first two phases of this study, a new paradigm has been developed
      which may provide further insight into affective behavioral biases. The Split Reversals task
      is a pavlovian reversal-learning task which allows the assessment of responses to expected
      and unexpected punishment and reward cues. Previous research with this task has demonstrated
      that reduction of serotonin in healthy individuals removes a disproportionate inability to
      predict punishment at baseline. In other words, serotonin reduction removes a positive bias
      on this task. . This is consistent with the observed removal of a positive bias on the AGNG
      following TD. However, on the split reversals task this positive bias is revealed by an
      inability to process negative stimuli at baseline, which is improved, rather than a bias
      towards positive stimuli which is diminished, by TD. As such, the new task provides a
      different direction from which to consider the emotional biases observed in affective
      disorders. We have suggested that the bias on the new task reflects a serotonin-mediated
      suppression of responses to negative stimuli in healthy individuals which, in turn, promote
      resilience to affective disorders. Serotonin reduction via TD hence removes this bias. That
      this task may therefore be sensitive to cognitive biases resulting from resilience
      mechanisms.

      Similarly, fear potentiated startle which has been shown to be sensitive to the symptoms of
      anxiety has been shown to be reduced by the elevation of 5-HT via two week citalopram
      treatment. This is consistent with reduced processing of negative information following 5-HT
      increase (Grillon et al 2009). We predict that reducing 5-HT via TD will have the opposite
      effect and increase the duration of fear potentiated startle processing. This would provide
      an indirect link between reduced 5-HT and anxiety disorders. As such, we include this task in
      a new phase of this protocol.

      In addition these behavioural TD findings, this task has been neuroimaged (fMRI) in healthy
      individuals. As predicted, the striatum was shown to be involved in reward processing, whilst
      the amygdala was shown to be involved in punishment processing. A subproject of this study
      will therefore attempt to extend the prior findings from the split reversals task (and
      reconcile them with the AGNG findings) by examining healthy individuals completing the task
      whilst undergoing both serotonin manipulation (TD) and fMRI. This subproject will be
      initially restricted to healthy individuals and should provide us with further insight into
      the neural substrates involved in serotonergic inhibition of aversive processing highlighted
      by the first phase of this study. This will also provide a basis from which to consider
      potential future study with the same task in MDD subjects undergoing TD.

      There may well be a genetic basis to these phenomena. It is known that the functional variant
      in the promoter region of the serotonin transporter gene (5-HTTLPR) is partly responsible for
      determining how individuals respond to TD. In fact, recently reported that carriers of the
      short 5-HTTLPR allele showed impaired recognition of fearful faces following TD.
    

Keywords: Major Depressive Disorder; Serotonin; Functional MRI; Genotype; Negative Affect; MDD; Healthy Volunteer; HV