Ignite Creation Date:
2024-05-05 @ 11:44 AM
Last Modification Date:
2024-10-26 @ 9:12 AM
Study NCT ID:
NCT00116077
Status:
COMPLETED
Last Update Posted:
2017-07-02
First Post:
2005-06-26
Brief Title:
Dopamine Receptor Imaging in Mood Disorders
Sponsor:
National Institute of Mental Health NIMH
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Dopamine Receptor Imaging in Mood Disorders
Status:
COMPLETED
Status Verified Date:
2010-11-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 volunteers 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 23 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
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 volunteers 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 23 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 eg pramapaxil and DA reuptake inhibitors eg nomiphensine exert antidepressant effects 3 Many somatic antidepressant therapies enhance D23 receptor sensitivity in limbic structures andor 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 11CSCH 23390 in the frontal cortex of bipolar subjects However 11CSCH 23390 has some affinity for 5-HT2 receptors in the frontal cortex De Keyser et al1988 so the specificity of this result remains unclear In contrast 11CNNC 112 is selective for D1 receptors and shows sufficient receptor selectivity to access D1 receptor binding in the frontal cortex in mood disorders
Previous studies of D2 receptors using 11Craclopride 11CNMSP and 123IIBZM have been limited by the lack of sensitivity of those radioligands to receptors outside the striatum Striatal D2 receptor binding has been reported to be abnormally increased in psychotic bipolar subjects relative to both controls and non-psychotic bipolar subjects using 11CNMSP Pearlson et al 1995 and unaltered in subjects with Major Depressive Disorder MDD compared to controls in two studies using 123IIBZM Klimke et al 1999 Parsey et al 2001 An increased basal ganglia-to-cerebellum ratio of D2 receptor binding using 123IIBZM has been reported in depressed MDD subjects compared to controls DHanenen and Bossuyt 1994 Ebert et al 1996 SPECT imaging studies show that 123IIBZM binding to striatal D23 receptors is abnormally elevated in MDD Although these studies were confounded by medication effects and small subject samples because 123IIBZM 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 11CNNC 112 and 18Ffallypride binding to assess D1 and D23 receptor binding potential BP respectively in unmedicated depressed subjects part A The 11C-Raclopride Bolus plus constant infusion BI PET scan will assess D2 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 D23 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 D1 receptor binding in BD subjects and performance on working memory and attention based tasks
Hypothesis 1a D1 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 D23 receptor binding severity of depression psychomotor retardation and anhedonia in depressed subjects with BD or MDD compared to healthy controls
Hypothesis 2a Baseline 18Ffallypride 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 D23 receptor binding will correlate positively with ratings of anhedonia and depressed mood and negatively with psychomotor performance speed
Hypothesis 2c Baseline 11C 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 11C 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 D1 and D23 receptor binding between MDD and BD subjects
B To investigate whether polymorphisms for the D1 or the D23 receptor gene may be associated with differences in receptor BP
C To assess the relationship between 11CNNC binding to D1 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
In more direct assessments of DA receptor pharmacology Suhara et al 1992 reported an abnormal decrease in D1 receptor binding using 11CSCH 23390 in the frontal cortex of bipolar subjects However 11CSCH 23390 has some affinity for 5-HT2 receptors in the frontal cortex De Keyser et al1988 so the specificity of this result remains unclear In contrast 11CNNC 112 is selective for D1 receptors and shows sufficient receptor selectivity to access D1 receptor binding in the frontal cortex in mood disorders
Previous studies of D2 receptors using 11Craclopride 11CNMSP and 123IIBZM have been limited by the lack of sensitivity of those radioligands to receptors outside the striatum Striatal D2 receptor binding has been reported to be abnormally increased in psychotic bipolar subjects relative to both controls and non-psychotic bipolar subjects using 11CNMSP Pearlson et al 1995 and unaltered in subjects with Major Depressive Disorder MDD compared to controls in two studies using 123IIBZM Klimke et al 1999 Parsey et al 2001 An increased basal ganglia-to-cerebellum ratio of D2 receptor binding using 123IIBZM has been reported in depressed MDD subjects compared to controls DHanenen and Bossuyt 1994 Ebert et al 1996 SPECT imaging studies show that 123IIBZM binding to striatal D23 receptors is abnormally elevated in MDD Although these studies were confounded by medication effects and small subject samples because 123IIBZM 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 11CNNC 112 and 18Ffallypride binding to assess D1 and D23 receptor binding potential BP respectively in unmedicated depressed subjects part A The 11C-Raclopride Bolus plus constant infusion BI PET scan will assess D2 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 D23 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 D1 receptor binding in BD subjects and performance on working memory and attention based tasks
Hypothesis 1a D1 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 D23 receptor binding severity of depression psychomotor retardation and anhedonia in depressed subjects with BD or MDD compared to healthy controls
Hypothesis 2a Baseline 18Ffallypride 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 D23 receptor binding will correlate positively with ratings of anhedonia and depressed mood and negatively with psychomotor performance speed
Hypothesis 2c Baseline 11C 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 11C 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 D1 and D23 receptor binding between MDD and BD subjects
B To investigate whether polymorphisms for the D1 or the D23 receptor gene may be associated with differences in receptor BP
C To assess the relationship between 11CNNC binding to D1 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 05-M-0169 | None | None | None |