Dopamine Receptor Imaging in Mood Disorders
Condition: Mood Disorders; Depressive Disorder, Major; Bipolar Disorder
MeSH terms: Depressive Disorder; Depression; Bipolar Disorder; Mood Disorders; Depressive Disorder, Major
Study type: Observational

Summary: 
      This study seeks to increase the understanding of dopamine receptor function in the brain
      during major depressive disorder and bipolar depression, as well as genetic changes that may
      be behind changes in those receptors' actions. Dopamine is a natural messenger in the brain,
      involved in reward, motivation, and mood.

      Volunteers aged 18 to 55 who have primary major depressive disorder and those who have
      bipolar depression (20 in each group), who are not HIV positive and do not have AIDS, and who
      are not pregnant or breastfeeding may be eligible for this study.

      A telephone interview will be held, for patients to answer standardized questions about
      psychiatric or medical symptoms they may have experienced during their lifetime. Those
      eligible for the study will undergo interviews and laboratory tests. A psychiatric interview
      and clinical assessment will collect various data. Patients will undergo the following
      procedures and tests:

        -  A brief neurological examination

        -  A one-minute electrocardiogram to measure electrical activity of the heart.

        -  Laboratory tests measuring several substances in the blood and urine.

        -  Pregnancy test.

      A magnetic resonance imaging (MRI) scan will be done to create an image of the volunteer's
      brain structure. The technique of MRI uses a strong magnetic field and radio waves to obtain
      images of body organs and tissues. During the MRI scan, volunteers will lie still on a table
      that will slide into the scanner for 30 minutes and in some cases up to but no more than 90
      minutes. Volunteers will be asked to lie as still as possible during the procedure. Then a
      PET system will create two images of brain blood flow-one of brain dopamine 1 receptor and
      one of dopamine 2/3 receptor binding. Volunteers will be given a radiotracer, a tiny amount
      of a drug that can be detected by a special camera in the PET scanner. A tiny flexible tube
      will be placed in the vein of one arm during each PET scan but during the MRI scan.
      Volunteers will be asked to lie still on the PET scanner table. A mask with large holes for
      eyes, ears, and mouth will be placed over the head, to keep the head from moving. After
      radiotracer injections are given, the PET scanner will create brain images. There may be two
      PET scanning sessions, each requiring about 3 hours of scanning. During only one of these
      there will be breaks. At the end of the scanning session, volunteers will be asked to drink
      several glasses of water and urinate immediately, to reduce radiation exposure to the bladder
      wall.

      Genetic screening will help to enhance researchers' understanding of the role of dopamine
      receptors in depression. A small blood sample, about 2 tablespoons, will be collected, to
      isolate DNA from blood cells. Some of the blood samples or DNA may be stored for future
      studies, but those samples will remain coded, so participants will not be identified. This
      study will not have a direct benefit for participants. However, the results may provide
      knowledge to help people in the future. This study does involve compensation.
    

Detailed description: 
      The dopaminergic projections from the substantia nigra and the ventral tegmental area into
      the ventral striatum and medial prefrontal cortex (mPFC) play major roles in the neural
      processing underlying motivated behavior. Hypofunction of this system is hypothesized to
      underlie the anhedonia, psychomotor slowing and amotivation that characterize major
      depressive disorder (MDD; (Fibiger, 1991; Swerdlow and Koob, 1987). A variety of indirect
      evidence supports this hypothesis (Wilner, 1995) as: 1) Cerebrospinal fluid (CSF)
      concentrations of the DA metabolite, homovanillic acid, are reduced in nondelusional,
      depressives. 2) Dextroamphetamine (AMPH) improves mood in depressed patients, and direct DA
      receptor agonists (e.g. pramapaxil) and DA reuptake inhibitors (e.g. nomiphensine) exert
      antidepressant effects. 3) Many somatic antidepressant therapies enhance D(2/3) receptor
      sensitivity in limbic structures and/or increase interstitial DA concentrations in the mPFC
      and accumbens in rats. 4) Conditions in which DA is depleted increase the risk for developing
      major depression, and DA receptor antagonist administration produces dysphoria, avolition and
      fatigue in healthy humans.

      In more direct assessments of DA receptor pharmacology, Suhara et al. (1992) reported an
      abnormal decrease in D1 receptor binding using [(11)C]SCH 23390 in the frontal cortex of
      bipolar subjects. However, [(11)C]SCH 23390 has some affinity for 5-HT(2) receptors in the
      frontal cortex (De Keyser et al.,1988) so the specificity of this result remains unclear. In
      contrast, [(11)C]NNC 112 is selective for D1 receptors and shows sufficient receptor
      selectivity to access D(1) receptor binding in the frontal cortex in mood disorders.

      Previous studies of D(2) receptors using [(11)C]raclopride, [11C]NMSP and [(123)I]IBZM have
      been limited by the lack of sensitivity of those radioligands to receptors outside the
      striatum. Striatal D(2) receptor binding has been reported to be abnormally increased in
      psychotic bipolar subjects relative to both controls and non-psychotic bipolar subjects using
      [(11)C]NMSP (Pearlson et al., 1995) and unaltered in subjects with Major Depressive Disorder
      (MDD) compared to controls in two studies using [(123)I]IBZM (Klimke et al., 1999; Parsey et
      al., 2001). An increased basal ganglia-to-cerebellum ratio of D(2) receptor binding using
      [(123)I]IBZM has been reported in depressed MDD subjects compared to controls (D'Hanenen and
      Bossuyt, 1994; Ebert et al., 1996). SPECT imaging studies show that [(123)I]IBZM binding to
      striatal D(2/3) receptors is abnormally elevated in MDD. Although these studies were
      confounded by medication effects and small subject samples, because [(123)I]IBZM binding is
      sensitive to competition from endogenous DA, this abnormality could reflect reduced
      intrasynaptic DA levels in the striatum of MDD subjects.

      The current study will address the limitations of the previous studies by characterizing D1
      and D2 receptor binding in depression in extrastriatal, as well as striatal regions. PET
      measures of [11C]NNC 112 and [(18)F]fallypride binding to assess D(1) and D(2/3) receptor
      binding potential (BP), respectively, in unmedicated depressed subjects (part A). The
      11C-Raclopride Bolus plus constant infusion (B/I) PET scan will assess D(2) receptor binding
      in vivo in the striatum while the subjects perform a monetary reward task, specifically
      designed to induce changes in the striatal dopaminergic transmission (part B).

      The application of high resolution 3D PET and MRI-based region-of-interest analysis will
      permit specific assessment of abnormalities of the D(2/3) receptor system in currently
      depressed individuals with MDD and BD and of correlations with clinical ratings in ventral
      and dorsal striatum as well as in extrastriatal areas such as the amygdala, anterior
      cingulate cortex, medial prefrontal cortex and orbital cortex. Possible relationships of
      polymorphisms in the genes coding for elements of the dopaminergic system as well as the
      dopamine receptors being studied in MDD or BD with the level of binding detected will be
      investigated collecting preliminary data.

      SPECIFIC AIMS

        1. Assess D(1) receptor binding in BD subjects and performance on working memory and
           attention based tasks.

           Hypothesis 1a. D(1) receptor binding will be decreased in the frontal cortex and
           unaltered in the striatum of BD subjects compared to healthy controls.

           Hypothesis 1b. Working memory and attention task performance impairments will correlate
           with changes in binding levels.

        2. Evaluate striatal and extrastriatal D(2/3) receptor binding, severity of depression,
           psychomotor retardation and anhedonia in depressed subjects with BD or MDD compared to
           healthy controls.

      Hypothesis 2a. Baseline [(18)F]fallypride binding in the ventral striatum, amygdala, medial
      thalamus, orbital cortex and subgenual PFC will be increased in depressives relative to
      controls.

      Hypothesis 2b. The ventral striatal D(2/3) receptor binding will correlate positively with
      ratings of anhedonia and depressed mood, and negatively with psychomotor performance speed.

      Hypothesis 2c. Baseline [(11)C] raclopride binding in the ventral striatum will be increased
      in depressed patients and this increase will correlate negatively with the subjective
      evaluation of rewarding stimuli and mood.

      Hypothesis 2d. The monetary reward task will induce a reduction of [(11)C] raclopride
      striatal binding, which will be larger in controls than in depressed patients and correlate
      negatively with anhedonia scores.

      Secondary Aims: A. To explore differences in D(1) and D(2/3) receptor binding between MDD and
      BD subjects.

      B. To investigate whether polymorphisms for the D(1) or the D(2/3) receptor gene may be
      associated with differences in receptor BP.

      C. To assess the relationship between [11C]NNC binding to D(1) receptors and performance on
      working memory and attention based tasks from the CANTAB (Cambridge Cognition, UK), including
      the Rapid Visual Information Processing test (RVIP) the Spatial Working Memory test (SWM) and
      the Pattern Recognition Memory test (PRM).
    

Keywords: PET; [C-11] NNC-112; [F-18] Fallypride; Dopamine Receptors; Mood Disorders; DA Receptors; Major Depressive Disorder; Bipolar Disorder; MDD; Bipolar Depression; Healthy Volunteer; HV