DepressionNCT00050700
Brain Imaging in Depression
An observational study of Depression and Bipolar Disorder, run by National Institute of Mental Health (NIMH) at 1 site in United States.
Trial summary
The purpose of this study is to use brain imaging technology to examine the role of certain brain receptors and the nervous system chemical acetylcholine in major depression. The cholinergic system involves the regulation of neurotransmitters and the brain receptors to which they bind. Read more about this study
- Who is it for?
- Ages 18 to 45 yearsHealthy volunteers can take part
- Conditions the study is for
- Depression, Bipolar Disorder
- How many people
- 107 participants
- Where
- 1 siteUnited States
- Study dates
- 16 Dec 2002to 14 May 2010
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Thirty subjects (ages 18-45) male and female will be selected, with primary MDD currently depressed as defined by DSM-IV criteria for recurrent MDD and current HDRS score in the moderately-to-severely depressed range (greater than 18) and who have a first degree relative with MDD but no first degree relatives with mania, alcoholism, or antisocial personality disorder.
- Thirty subjects (ages 18-45) male and female will be selected who meet DSM-IV criteria for bipolar I or II disorder and are currently depressed, with HDRS score in the moderately-to-severely depressed range (greater than 18). Subjects may be inpatients or outpatients. Because effective treatment will not be discontinued for the purposes of this protocol, subjects will be identified who have never been treated or who have discontinued medication due to lack of efficacy, noncompliance, physician order, or other reasons prior to study entry.
- Thirty subjects (ages 18-45) male and female who have not met criteria for any major psychiatric disorder will be selected. From this large sample a control subject will be matched to each depressed subject for age, gender, handedness and stage of menstrual cycle. The control subjects will have no known first degree relatives with mood disorders.
Who cannot join
- Subjects must not have taken antidepressant or other medications likely to alter monoamine neurochemistry or cerebrovascular function for at least 3 weeks (8 weeks for fluoxetine and for any drug with known anticholinergic effects) prior to scanning. Because effective medications will not be discontinued for the purposes of this study, subjects will be identified who have never been treated or who have discontinued medication due to lack of efficacy, noncompliance, physician order or other reasons prior to study entry. Subjects will also be excluded if they: a) serious suidical ideation or behavior - 1) thoughts of suicide within the past three months which are accompanied by intet to harm oneself, serious consideration of means or plan to attempt suicide, evidence of arranging for a suicide attemp (e.g. giving away prized possessions, updating a will) or clear desire to commit suicide; 2) suicide attempts within the previous one year; or 3) a current plan to inflict self harm or physical evidence suspicious for having engaged in a suicide attempt.
- Subjects will also be excluded if they had any significant comorbid condition in the last year, c) psychosis to the extent that the ability to provide informed consent is in doubt, d) history of any major psychiatric disorder (other than the target mood disorder) arising temporally before the initial mood episode, e) medical or neurological illnesses (i.e. seizure disorder, a coma in past) likely to affect physiology or anatomy, f) a history of drug or alcohol abuse within 1 year or a lifetime history of alcohol or drug dependence (DSM IV criteria), g) are HIV positive or have AIDS, h) current pregnancy (documented by history and pregnancy testing prior to scanning), i) current breast feeding, j) general MRI exclusion criteria which include the subject having a pacemaker or significant claustrophobia and k) if they are smokers.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Muscarinic Cholinergic Receptor Imaging in Depression
The purpose of this study is to use brain imaging technology to examine the role of certain brain receptors and the nervous system chemical acetylcholine in major depression.
The cholinergic system involves the regulation of neurotransmitters and the brain receptors to which they bind. Evidence suggests that the cholinergic system may play a role in the development of depression. Acetylcholine is a neurotransmitter that binds to certain brain receptors called muscarinic cholinergic receptors. Cholinomimetic drugs (drugs that stimulate the cholinergic system) often exacerbate depressive symptoms in people with mood disorders and in healthy individuals. This increase in depressive symptoms may be caused by stimulation of muscarinic acetylcholine receptors (mAChRs), but further study is needed to confirm this. This study will use positron emission tomography (PET) and magnetic resonance imaging (MRI) to study the function of mAChRs in individuals with depression.
Participants in this study will undergo a physical examination, psychiatric interviews, neuropsychological tests, PET and MRI scans, and rating scales of depression, anxiety, and negative thinking symptoms. Questions about behavior and functioning will be asked and blood samples will be collected for genetic analysis.
Read the detailed description
Several paths of evidence converge in implicating a role for the cholinergic system in the pathophysiology of affective illness. In both unipolar depressed and euthymic bipolar subjects, cholinomimetic drugs (i.e., muscarinic agonists, acetylcholinesterase inhibitors) exacerbate depressive signs and symptoms such as dysphoria, psychomotor retardation, impairment of attention and memory, hypothalamic pituitary adrenal axis hyperactivity and sleep EEG abnormalities. In healthy subjects, the acetylcholinesterase inhibitor physostigmine elicits a range of depressive symptoms including dysphoria, anergia, psychomotor slowing, emotional lability, sleep disturbances, memory and concentration impairment, and with higher doses, tearfulness and depression. These effects have been shown to reflect stimulation of muscarinic receptors. Cholinomimetics also exacerbate behavioral despair in putative animal models of depression. Conversely, the anticholinergic agent biperidine improved symptoms of depression in a placebo controlled study. Moreover, muscarinic cholinomimetics and a choline rich nutrient, lecithin (phosphatidylcholine) exert antimanic effects in bipolar subjects.
Potentially consistent with these observations, depressed subjects exhibit hypersensitivity to cholinomimetic agents. Administration of muscarinic cholinergic agonists, ACh releasing agents or acetylcholinesterase inhibitors induce exaggerated effects on REM density and latency in depressed subjects than in healthy controls. In addition, both manic and depressed bipolar subjects show increased pupillary sensitivity to the muscarinic cholinergic agonist pilocarpine relative to controls.
Despite the data implicating the mAChR receptor system in mood disorders, no direct in vivo investigations of the central mAChR have been performed in depressed subjects. A novel PET radioligand, [(18)F]FP-TZTP was recently developed by Eckelman as a selective agonist of M(2) receptors. Because the M(2) receptor functions predominately as a presynaptic release-controlling autoreceptor, decreased distribution volume (V) of this receptor could conceivably give rise to increased postsynaptic muscarinic receptor sensitivity.
This application proposes a pilot PET study of M(2) receptor distribution volume in currently depressed subjects with major depressive disorder (n=30), currently depressed subjects with bipolar disorder (n=30), and psychiatrically healthy controls (n=30). The proposed pilot study will test the central hypothesis that M(2) receptor V is decreased in regions where they are primarily located presynaptically in depressed subjects relative to healthy controls. The proposed study will advance knowledge regarding the pathophysiology of depression.
- Conditions
- Depression, Bipolar Disorder
- Keywords
- PET, [18F]FP-TZTP, Bipolar Disorder, Major Depressive Disorder, Muscarinic 2 Receptors
- Medical subject headings
- Depression, Bipolar Disorder, Depressive Disorder, Major
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Dec 2002 (estimated)
- Study start16 Dec 2002
- Study completion14 May 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for DepressionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Enrolment
- 107 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institute of Mental Health (NIMH)
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00050700
- Sponsor's protocol ID
- 030001
- Other IDs
- 03-M-0001
- Status last verified
- 14 May 2010
- First submitted
- 17 Dec 2002
- Last updated
- 2 Jul 2017
- Results posted
- No
Publications
Allen TG. The role of N-, Q- and R-type Ca2+ channels in feedback inhibition of ACh release from rat basal forebrain neurones. J Physiol. 1999 Feb 15;515 ( Pt 1)(Pt 1):93-107. doi: 10.1111/j.1469-7793.1999.093ad.x.
PubMed 9925881Arango V, Underwood MD, Boldrini M, Tamir H, Kassir SA, Hsiung S, Chen JJ, Mann JJ. Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology. 2001 Dec;25(6):892-903. doi: 10.1016/S0893-133X(01)00310-4.
PubMed 11750182Baratti CM, Opezzo JW, Kopf SR. Facilitation of memory storage by the acetylcholine M2 muscarinic receptor antagonist AF-DX 116. Behav Neural Biol. 1993 Jul;60(1):69-74. doi: 10.1016/0163-1047(93)90742-z.
PubMed 8216161
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Muscarinic Cholinergic Receptor Imaging in Depression
- ClinicalTrials.gov ID
- NCT00050700
- Acronym / sponsor ID
- 030001
- Conditions
- Depression, Bipolar Disorder
- Keywords
- PET, [18F]FP-TZTP, Bipolar Disorder, Major Depressive Disorder, Muscarinic 2 Receptors
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 107 participants (actual)
- Lead sponsor
- National Institute of Mental Health (NIMH)US National Institutes of Health
- Study start
- 16 Dec 2002
- Study completion
- 14 May 2010
- First posted
- 18 Dec 2002 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to use brain imaging technology to examine the role of certain brain receptors and the nervous system chemical acetylcholine in major depression.
The cholinergic system involves the regulation of neurotransmitters and the brain receptors to which they bind. Evidence suggests that the cholinergic system may play a role in the development of depression. Acetylcholine is a neurotransmitter that binds to certain brain receptors called muscarinic cholinergic receptors. Cholinomimetic drugs (drugs that stimulate the cholinergic system) often exacerbate depressive symptoms in people with mood disorders and in healthy individuals. This increase in depressive symptoms may be caused by stimulation of muscarinic acetylcholine receptors (mAChRs), but further study is needed to confirm this. This study will use positron emission tomography (PET) and magnetic resonance imaging (MRI) to study the function of mAChRs in individuals with depression.
Participants in this study will undergo a physical examination, psychiatric interviews, neuropsychological tests, PET and MRI scans, and rating scales of depression, anxiety, and negative thinking symptoms. Questions about behavior and functioning will be asked and blood samples will be collected for genetic analysis.
Detailed description
Several paths of evidence converge in implicating a role for the cholinergic system in the pathophysiology of affective illness. In both unipolar depressed and euthymic bipolar subjects, cholinomimetic drugs (i.e., muscarinic agonists, acetylcholinesterase inhibitors) exacerbate depressive signs and symptoms such as dysphoria, psychomotor retardation, impairment of attention and memory, hypothalamic pituitary adrenal axis hyperactivity and sleep EEG abnormalities. In healthy subjects, the acetylcholinesterase inhibitor physostigmine elicits a range of depressive symptoms including dysphoria, anergia, psychomotor slowing, emotional lability, sleep disturbances, memory and concentration impairment, and with higher doses, tearfulness and depression. These effects have been shown to reflect stimulation of muscarinic receptors. Cholinomimetics also exacerbate behavioral despair in putative animal models of depression. Conversely, the anticholinergic agent biperidine improved symptoms of depression in a placebo controlled study. Moreover, muscarinic cholinomimetics and a choline rich nutrient, lecithin (phosphatidylcholine) exert antimanic effects in bipolar subjects.
Potentially consistent with these observations, depressed subjects exhibit hypersensitivity to cholinomimetic agents. Administration of muscarinic cholinergic agonists, ACh releasing agents or acetylcholinesterase inhibitors induce exaggerated effects on REM density and latency in depressed subjects than in healthy controls. In addition, both manic and depressed bipolar subjects show increased pupillary sensitivity to the muscarinic cholinergic agonist pilocarpine relative to controls.
Despite the data implicating the mAChR receptor system in mood disorders, no direct in vivo investigations of the central mAChR have been performed in depressed subjects. A novel PET radioligand, [(18)F]FP-TZTP was recently developed by Eckelman as a selective agonist of M(2) receptors. Because the M(2) receptor functions predominately as a presynaptic release-controlling autoreceptor, decreased distribution volume (V) of this receptor could conceivably give rise to increased postsynaptic muscarinic receptor sensitivity.
This application proposes a pilot PET study of M(2) receptor distribution volume in currently depressed subjects with major depressive disorder (n=30), currently depressed subjects with bipolar disorder (n=30), and psychiatrically healthy controls (n=30). The proposed pilot study will test the central hypothesis that M(2) receptor V is decreased in regions where they are primarily located presynaptically in depressed subjects relative to healthy controls. The proposed study will advance knowledge regarding the pathophysiology of depression.
Study design
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- Thirty subjects (ages 18-45) male and female will be selected, with primary MDD currently depressed as defined by DSM-IV criteria for recurrent MDD and current HDRS score in the moderately-to-severely depressed range (greater than 18) and who have a first degree relative with MDD but no first degree relatives with mania, alcoholism, or antisocial personality disorder.
- Thirty subjects (ages 18-45) male and female will be selected who meet DSM-IV criteria for bipolar I or II disorder and are currently depressed, with HDRS score in the moderately-to-severely depressed range (greater than 18). Subjects may be inpatients or outpatients. Because effective treatment will not be discontinued for the purposes of this protocol, subjects will be identified who have never been treated or who have discontinued medication due to lack of efficacy, noncompliance, physician order, or other reasons prior to study entry.
- Thirty subjects (ages 18-45) male and female who have not met criteria for any major psychiatric disorder will be selected. From this large sample a control subject will be matched to each depressed subject for age, gender, handedness and stage of menstrual cycle. The control subjects will have no known first degree relatives with mood disorders.
Key exclusion criteria (2 listed)
- Subjects must not have taken antidepressant or other medications likely to alter monoamine neurochemistry or cerebrovascular function for at least 3 weeks (8 weeks for fluoxetine and for any drug with known anticholinergic effects) prior to scanning. Because effective medications will not be discontinued for the purposes of this study, subjects will be identified who have never been treated or who have discontinued medication due to lack of efficacy, noncompliance, physician order or other reasons prior to study entry. Subjects will also be excluded if they: a) serious suidical ideation or behavior - 1) thoughts of suicide within the past three months which are accompanied by intet to harm oneself, serious consideration of means or plan to attempt suicide, evidence of arranging for a suicide attemp (e.g. giving away prized possessions, updating a will) or clear desire to commit suicide; 2) suicide attempts within the previous one year; or 3) a current plan to inflict self harm or physical evidence suspicious for having engaged in a suicide attempt.
- Subjects will also be excluded if they had any significant comorbid condition in the last year, c) psychosis to the extent that the ability to provide informed consent is in doubt, d) history of any major psychiatric disorder (other than the target mood disorder) arising temporally before the initial mood episode, e) medical or neurological illnesses (i.e. seizure disorder, a coma in past) likely to affect physiology or anatomy, f) a history of drug or alcohol abuse within 1 year or a lifetime history of alcohol or drug dependence (DSM IV criteria), g) are HIV positive or have AIDS, h) current pregnancy (documented by history and pregnancy testing prior to scanning), i) current breast feeding, j) general MRI exclusion criteria which include the subject having a pacemaker or significant claustrophobia and k) if they are smokers.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jul 2017.
- Background: PubMed 9925881Allen TG. The role of N-, Q- and R-type Ca2+ channels in feedback inhibition of ACh release from rat basal forebrain neurones. J Physiol. 1999 Feb 15;515 ( Pt 1)(Pt 1):93-107. doi: 10.1111/j.1469-7793.1999.093ad.x.
- Background: PubMed 11750182Arango V, Underwood MD, Boldrini M, Tamir H, Kassir SA, Hsiung S, Chen JJ, Mann JJ. Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology. 2001 Dec;25(6):892-903. doi: 10.1016/S0893-133X(01)00310-4.
- Background: PubMed 8216161Baratti CM, Opezzo JW, Kopf SR. Facilitation of memory storage by the acetylcholine M2 muscarinic receptor antagonist AF-DX 116. Behav Neural Biol. 1993 Jul;60(1):69-74. doi: 10.1016/0163-1047(93)90742-z.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Depression and Bipolar Disorder, run by National Institute of Mental Health (NIMH) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00050700, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jul 2017.