Bipolar Affective DisorderPhase 2NCT00327756
Mitochondrial Dysfunction in the Pathophysiology and Treatment of Bipolar Disorder
A Phase 2 study testing Coenzyme Q10 in people with Bipolar Affective Disorder and Depression, run by National Institute of Mental Health (NIMH) at 1 site in United States.
Trial summary
This study will examine whether mitochondrial function is impaired in patients with bipolar disorder. Mitrochondria are small organelles inside the cell that are responsible for energy production. Recent studies in animals and humans suggest that abnormalities of mitrochondria may be involved in bipolar depression. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Bipolar Affective Disorder, Depression
- What is being tested?
- Coenzyme Q10
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- May 2006to May 2009
- Phase
- Phase 2
- 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 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Male or female subjects, 18 to 65 years of age.
- Female subjects of childbearing potential must be using a medically accepted means of contraception.
- Each subject must understand the nature of the study and must sign an informed consent document.
- Subjects must fulfill the criteria for Bipolar disorder depressed without psychotic features including rapid cycling as defined in DSM-IV based on clinical assessment and confirmed by structured diagnostic interview SCID-P.
- Subjects must have an initial score at Visit 1 and Visit 2 of at least 16 on the MADRS
- In bipolar II disorder, subjects must have experienced, in the opinion of the investigator, at least two previous hypomanic and two major depressive episodes as defined in DSM-IV.
- Current major depressive episode at least 4 weeks in duration.
Who cannot join
- Subjects who are currently on a mood stabilizer for maintenance treatment and are benefiting from it.
- Current diagnosis of primary anxiety disorder necessitating treatment (subjects with OCD will be excluded).
- Presence of psychotic features
- Participation in a clinical trial of another investigational drug within 1 month prior to study entry (Visit 1).
- Female subjects who are either pregnant or nursing.
- Serious, unstable illnesses including hepatic, renal, gastroenterological, respiratory, cardiovascular (including ischemic heart disease), endocrinology, neurological, immunologic, or hematological disease.
Show all 24Show fewer
- Subjects diagnosed with a mitochondrial disorder.
- Subjects taking other putative mitochondrial enhancers (e.g., vitamin E, carnitine, creatine, Vit complex B, pramipexole; see Appendix B) by the time of randomization (Visit 2).
- Subjects taking Statins
- Subjects with Diabetes Mellitus (Type I and Type II)
- Subjects with a history of clotting disorders or needing anticoagulants e.g. warfarin.
- Subjects with history of deep vein thrombosis or the following risk factors for DVTs, smoking and/or contraceptives (30 days before Visit 2).
- Subjects with uncorrected hypothyroidism or hyperthyroidism.
- Subjects with one or more seizures.
- Documented history of hypersensitivity or intolerance to CoQ10.
- DSM-IV substance abuse (except caffeine) within the past 12 months, 1 month for nicotine.
- DSM-IV lifetime substance dependence (except caffeine).
- Treatment with an injectable depot neuroleptic within less than one dosing interval prior to Visit 2.
- Treatment with a reversible MAOI, guanethidine, or guanadrel within 1 week prior to Visit 2.
- Treatment with fluoxetine within 6 weeks prior to Visit 2.
- Treatment with any other concomitant medication 1 day prior to Visit 2.
- Treatment with clozapine or ECT within 1 month prior to Visit 2.
- Judged clinically to be at serious suicidal risk.
- Healthy Control Sample: Twenty-six subjects (ages 18-65) who do not meet criteria for any major medical or psychiatric disorder (using SCID -NP) will undergo imaging and mitochondrial assay part of the study and serve as control group. Control subjects will be matched to bipolar subjects for age, gender, Body Mass Index (BMI) plus or minus 2.
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: An Investigation Examining the Evidence for Mitochondrial Dysfunction in the Pathophysiology and Treatment of Bipolar Disorder
This study will examine whether mitochondrial function is impaired in patients with bipolar disorder. Mitrochondria are small organelles inside the cell that are responsible for energy production. Recent studies in animals and humans suggest that abnormalities of mitrochondria may be involved in bipolar depression. The study will also examine whether the food supplement Coenzyme Q10 (CoQ10) improves mitochondrial function and symptoms such as depressed mood, low energy, anxiety or slowness in thinking and movements in bipolar patients. CoQ10 has been used to increase cell energy production and as an antioxidant. It has had some benefit in patients with Parkinson's disease and migraine and in prolonging survival in patients with cancer and heart failure.
Patients 18-65 years of age with bipolar disorder who are currently in a depressive episode of at least 4 weeks duration may be eligible for this study. The study has four phases, as follows:
Read more
Phase I: Medication Withdrawal
Patients taper off all psychotropic medications, usually over 1 to 2 weeks.
Phase II: Baseline Evaluation
After being off all medication for about 2 weeks, patients undergo the following procedures:
- Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). The two procedures are performed in an MRI scanner. Both tests use a strong magnetic field and radio waves to obtain images that provide information on brain anatomy and chemistry.
- Blood tests to assess mitochondrial function isolated from blood cells.
- Skin biopsy for tests of mitochondria. A small sample of skin tissue 5 x 5 millimeters is surgically removed.
Phase III: Administration of CoQ10 or Placebo
Participants are randomly assigned to take either CoQ10 or placebo (an inactive look-alike substance) twice a day by mouth. While taking the study medication, patients have the following procedures periodically:
- Rating scales for anxiety and depression and adverse events.
- Check of vital signs.
- Blood and urine sample collections.
Phase IV: Study Completion
At the end of the 8 weeks of treatment, patients have a physical examination and electrocardiogram, and the procedures in phase II are repeated. Participants may then receive short-term treatment (up to 12 weeks) with medications for bipolar depression, followed by referred to a community physician for long-term treatment.
...
Read the detailed description
Bipolar affective disorder is a common, severe, chronic and often life-threatening illness. The depressive phase contributes to the majority of morbidity and mortality in this illness. Impairments in physical and social functioning resulting from depression are often as severe as other chronic medical illnesses. Few of the treatments in use have resulted from an understanding of the pathophysiology of bipolar disorder. Undoubtedly, a greater understanding of the pathophysiology of bipolar disorder will lead to improved treatments.
Current theories of depression suggest that mood disorders are associated with impairments of cellular resilience and structural plasticity possibly a result of abnormal cellular energy metabolism. Studies with Magnetic Resonance Spectroscopy (MRS) in bipolar subjects show reduced brain intracellular pH and reduced ATP. Cellular energy generated by mitochondrial oxidative phosphorylation from glucose via the electron transport chain is stored as ATP, which provide neurons and glia with energy required to maintain their function. Mitochondrial dysfunction and its inability to compensate for increase in ATP demand might lead to impaired cellular resilience believed to be involved in the pathophysiology of bipolar disorder. Abnormal regulation of nuclear genes coding for mitochondrial proteins in the hippocampus of bipolar subjects provides further evidence of mitochondrial dysfunction in bipolar disorder.
Coenzyme Q10 (CoQ10) is an essential cofactor in the mitochondrial electron transport chain necessary for cellular energy generation. Exogenous administration of CoQ10 attenuates ATP depletion and has anti-oxidant properties. In light of the above evidence, we hypothesize that bipolar disorder is associated with mitochondrial dysfunction as evidenced by impaired brain energy metabolism and that administration of CoQ10, a mitochondrial enhancer, will restore mitochondrial function. To accomplish these objectives, we will compare mitochondrial functions in bipolar depressed subjects to 26 healthy controls matched for age, gender and BMI. Measures of mitochondrial function will include brain lactate levels (a product of anaerobic glycolysis) with H+ MRS, 2) assays of mitochondrial function in cultured fibroblasts and platelets, and 3) gene expression of mitochondrial and nuclear genes using a cDNA Microarray. Further, subjects with bipolar depression, ages 18 to 65 will be randomized to either CoQ10 (300-1200 mg/day) or placebo in a double-blind placebo controlled trial for a period of 8 weeks. Measures of mitochondrial function will be compared between subjects randomized to placebo or CoQ10 at baseline and at the end of the 8-week trial.
- Conditions
- Bipolar Affective Disorder, Depression
- Being tested
- Coenzyme Q10
- Keywords
- Depression, Magnetic Resonance Spectroscopy, Mitochondrial Enhancer, Manic Depressive, Bioenergetics, Bipolar Disorder, Manic Depression
- Medical subject headings
- Bipolar Disorder, Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Coenzyme Q10Drug
What is being measured
The primary outcome is the main question the study is designed to answer.
Compare brain lactate levels between healthy controls and subjects with bipolar depression and assess in subjects w/bipolar depression the effect of of CoQ10 admin compared to placebo on the brain lactate signal obtained w/MRS w/photic stimulation.
Measured: 8 weeks
Secondary outcomes (1)
To determine the antidepressant efficacy of CoQ10 compared to placebo in depressed subjects w/bipolar disorder by using the mean change in MADRS total score pre- and post-study.
Measured: 8-weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 May 2006 (estimated)
- Study startMay 2006
- Primary completionMay 2009
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 Bipolar Affective DisorderStudies of the same condition, open and under way.
- More trials run by National Institute of Mental Health (NIMH)The sponsor's other registered studies.
- 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
- Interventional
- Phase
- Phase 2
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 0 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
- NCT00327756
- Sponsor's protocol ID
- 060162
- Other IDs
- 06-M-0162
- Status last verified
- May 2009
- First submitted
- 18 May 2006
- Last updated
- 23 Nov 2011
- Results posted
- No
Publications
Arias-Mendoza F. In vivo magnetic resonance spectroscopy in the evaluation of mitochondrial disorders. Mitochondrion. 2004 Sep;4(5-6):491-501. doi: 10.1016/j.mito.2004.07.034. Epub 2004 Sep 30.
PubMed 16120408Baker SK, Tarnopolsky MA. Targeting cellular energy production in neurological disorders. Expert Opin Investig Drugs. 2003 Oct;12(10):1655-79. doi: 10.1517/13543784.12.10.1655.
PubMed 14519086Bertolino A, Frye M, Callicott JH, Mattay VS, Rakow R, Shelton-Repella J, Post R, Weinberger DR. Neuronal pathology in the hippocampal area of patients with bipolar disorder: a study with proton magnetic resonance spectroscopic imaging. Biol Psychiatry. 2003 May 15;53(10):906-13. doi: 10.1016/s0006-3223(02)01911-x.
PubMed 12742678
Study at a glance
From the registry record, last updated by the sponsor on 23 Nov 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Investigation Examining the Evidence for Mitochondrial Dysfunction in the Pathophysiology and Treatment of Bipolar Disorder
- ClinicalTrials.gov ID
- NCT00327756
- Acronym / sponsor ID
- 060162
- Conditions
- Bipolar Affective Disorder, Depression
- Keywords
- Depression, Magnetic Resonance Spectroscopy, Mitochondrial Enhancer, Manic Depressive, Bioenergetics, Bipolar Disorder, Manic Depression
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Withdrawn
- Enrolment
- 0 participants (actual)
- Lead sponsor
- National Institute of Mental Health (NIMH)US National Institutes of Health
- Study start
- May 2006
- Primary completion
- May 2009 (actual)
- First posted
- 19 May 2006 (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.
This study will examine whether mitochondrial function is impaired in patients with bipolar disorder. Mitrochondria are small organelles inside the cell that are responsible for energy production. Recent studies in animals and humans suggest that abnormalities of mitrochondria may be involved in bipolar depression. The study will also examine whether the food supplement Coenzyme Q10 (CoQ10) improves mitochondrial function and symptoms such as depressed mood, low energy, anxiety or slowness in thinking and movements in bipolar patients. CoQ10 has been used to increase cell energy production and as an antioxidant. It has had some benefit in patients with Parkinson's disease and migraine and in prolonging survival in patients with cancer and heart failure.
Patients 18-65 years of age with bipolar disorder who are currently in a depressive episode of at least 4 weeks duration may be eligible for this study. The study has four phases, as follows:
Phase I: Medication Withdrawal
Patients taper off all psychotropic medications, usually over 1 to 2 weeks.
Phase II: Baseline Evaluation
After being off all medication for about 2 weeks, patients undergo the following procedures:
- Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). The two procedures are performed in an MRI scanner. Both tests use a strong magnetic field and radio waves to obtain images that provide information on brain anatomy and chemistry.
- Blood tests to assess mitochondrial function isolated from blood cells.
- Skin biopsy for tests of mitochondria. A small sample of skin tissue 5 x 5 millimeters is surgically removed.
Phase III: Administration of CoQ10 or Placebo
Participants are randomly assigned to take either CoQ10 or placebo (an inactive look-alike substance) twice a day by mouth. While taking the study medication, patients have the following procedures periodically:
- Rating scales for anxiety and depression and adverse events.
- Check of vital signs.
- Blood and urine sample collections.
Phase IV: Study Completion
At the end of the 8 weeks of treatment, patients have a physical examination and electrocardiogram, and the procedures in phase II are repeated. Participants may then receive short-term treatment (up to 12 weeks) with medications for bipolar depression, followed by referred to a community physician for long-term treatment.
...
Detailed description
Bipolar affective disorder is a common, severe, chronic and often life-threatening illness. The depressive phase contributes to the majority of morbidity and mortality in this illness. Impairments in physical and social functioning resulting from depression are often as severe as other chronic medical illnesses. Few of the treatments in use have resulted from an understanding of the pathophysiology of bipolar disorder. Undoubtedly, a greater understanding of the pathophysiology of bipolar disorder will lead to improved treatments.
Current theories of depression suggest that mood disorders are associated with impairments of cellular resilience and structural plasticity possibly a result of abnormal cellular energy metabolism. Studies with Magnetic Resonance Spectroscopy (MRS) in bipolar subjects show reduced brain intracellular pH and reduced ATP. Cellular energy generated by mitochondrial oxidative phosphorylation from glucose via the electron transport chain is stored as ATP, which provide neurons and glia with energy required to maintain their function. Mitochondrial dysfunction and its inability to compensate for increase in ATP demand might lead to impaired cellular resilience believed to be involved in the pathophysiology of bipolar disorder. Abnormal regulation of nuclear genes coding for mitochondrial proteins in the hippocampus of bipolar subjects provides further evidence of mitochondrial dysfunction in bipolar disorder.
Coenzyme Q10 (CoQ10) is an essential cofactor in the mitochondrial electron transport chain necessary for cellular energy generation. Exogenous administration of CoQ10 attenuates ATP depletion and has anti-oxidant properties. In light of the above evidence, we hypothesize that bipolar disorder is associated with mitochondrial dysfunction as evidenced by impaired brain energy metabolism and that administration of CoQ10, a mitochondrial enhancer, will restore mitochondrial function. To accomplish these objectives, we will compare mitochondrial functions in bipolar depressed subjects to 26 healthy controls matched for age, gender and BMI. Measures of mitochondrial function will include brain lactate levels (a product of anaerobic glycolysis) with H+ MRS, 2) assays of mitochondrial function in cultured fibroblasts and platelets, and 3) gene expression of mitochondrial and nuclear genes using a cDNA Microarray. Further, subjects with bipolar depression, ages 18 to 65 will be randomized to either CoQ10 (300-1200 mg/day) or placebo in a double-blind placebo controlled trial for a period of 8 weeks. Measures of mitochondrial function will be compared between subjects randomized to placebo or CoQ10 at baseline and at the end of the 8-week trial.
Study design
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Male or female subjects, 18 to 65 years of age.
- Female subjects of childbearing potential must be using a medically accepted means of contraception.
- Each subject must understand the nature of the study and must sign an informed consent document.
- Subjects must fulfill the criteria for Bipolar disorder depressed without psychotic features including rapid cycling as defined in DSM-IV based on clinical assessment and confirmed by structured diagnostic interview SCID-P.
- Subjects must have an initial score at Visit 1 and Visit 2 of at least 16 on the MADRS
Key exclusion criteria (24 listed)
- Subjects who are currently on a mood stabilizer for maintenance treatment and are benefiting from it.
- Current diagnosis of primary anxiety disorder necessitating treatment (subjects with OCD will be excluded).
- Presence of psychotic features
- Participation in a clinical trial of another investigational drug within 1 month prior to study entry (Visit 1).
- Female subjects who are either pregnant or nursing.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Coenzyme Q10 | Drug | – |
Primary outcome
Compare brain lactate levels between healthy controls and subjects with bipolar depression and assess in subjects w/bipolar depression the effect of of CoQ10 admin compared to placebo on the brain lactate signal obtained w/MRS w/photic stimulation.
Time frame: 8 weeks
1 secondary outcome
To determine the antidepressant efficacy of CoQ10 compared to placebo in depressed subjects w/bipolar disorder by using the mean change in MADRS total score pre- and post-study.
Time frame: 8-weeks
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Nov 2011.
- Background: PubMed 16120408Arias-Mendoza F. In vivo magnetic resonance spectroscopy in the evaluation of mitochondrial disorders. Mitochondrion. 2004 Sep;4(5-6):491-501. doi: 10.1016/j.mito.2004.07.034. Epub 2004 Sep 30.
- Background: PubMed 14519086Baker SK, Tarnopolsky MA. Targeting cellular energy production in neurological disorders. Expert Opin Investig Drugs. 2003 Oct;12(10):1655-79. doi: 10.1517/13543784.12.10.1655.
- Background: PubMed 12742678Bertolino A, Frye M, Callicott JH, Mattay VS, Rakow R, Shelton-Repella J, Post R, Weinberger DR. Neuronal pathology in the hippocampal area of patients with bipolar disorder: a study with proton magnetic resonance spectroscopic imaging. Biol Psychiatry. 2003 May 15;53(10):906-13. doi: 10.1016/s0006-3223(02)01911-x.
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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?
A Phase 2 study testing Coenzyme Q10 in people with Bipolar Affective Disorder and Depression, 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 7 inclusion and 24 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: withdrawn, as of the sponsor's last update on 23 Nov 2011. 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.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
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.
What does the primary outcome measure?
Compare brain lactate levels between healthy controls and subjects with bipolar depression and assess in subjects w/bipolar depression the effect of of CoQ10 admin compared to placebo on the brain lactate signal obtained w/MRS w/photic stimulation. (time frame: 8 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00327756, 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 23 Nov 2011.