Bipolar DisorderPhase 2NCT00029458
Clozapine for Treatment-Resistant Mania
A Phase 2 study testing Clozapine in people with 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 evaluate the safety and effectiveness of clozapine as a treatment for the manic phase of bipolar disorder. A significant proportion of manic patients either do not respond adequately to conventional treatment or cannot tolerate the adverse effects associated with therapeutic doses of… Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Bipolar Disorder
- What is being tested?
- Clozapine
- How many people
- 42 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2002to Oct 2005
- 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 Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Males or females 18 to 65 years of age;
- Diagnosis: DSM-IV Bipolar I Disorder, current episode manic or mixed with or without psychotic features as determined by SCID-P. This criteria includes the following diagnoses: 296.4X, Bipolar I Disorder, Most Recent Episode Manic, and 296.6X, Bipolar I Disorder, Most Recent Episode Mixed;
- YMRS greater than or equal to 20 at Visits 1 and 2;
- No decrease in total score of YMRS of greater than or equal to 20% during washout (between Visits 1 and 2);
- Meet criteria for treatment resistance.
- Patients must have experienced at least two manic or mixed episodes within five years prior to study entry; DSM-IV rapid cyclers will be permitted to participate in this study;
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- Each patient must have a level of understanding sufficient to agree to all the tests required by the protocol;
- Each patient must understand the nature of the study and must sign an informed consent document. Before participating in this study, we will advise all patients to complete a NIH Advance Directive Form. However, completing a NIH Advanced Directive form is not a requirement for participating in this study.
- Previous lack of response (during a manic episode) to any two of the following antimanic agents: lithium, valproate, carbamazepine, oxcarbazepine, typical antipsychotic drug, or atypical antipsychotic drug (olanzapine, risperidone, ziprasidone, aripiprazole, quetiapine). If the subject has only taking one of these antimanic treatments, then the research physician may start one of them at NIH. Subjects not responding to a 3 week trial of an antimanic agent of their choice (at least a 50% decrease on the YMRS rating scale form baseline) will be eligible to be randomized if they continue to meet study criteria.
Who cannot join
- WBC count is less than 3500/mm(3) or history of a myeloproliferative disorder.
- History of meeting criteria for DSM-IV criteria for schizophrenia or other psychotic disorder;
- History of DSM-IV substance abuse or dependence, including alcohol within the last four weeks;
- Acute or unstable medical illnesses, (e.g., delirium, metastatic cancer, unstable diabetes, decompensated cardiac, hepatic, renal or pulmonary disease, or stroke or myocardial infarction within the last six months);
- Current pregnancy or plan to become pregnant during the first three months (the duration of the study) in woman of childbearing age; breast-feeding in woman with infants;
- Previous treatment with clozapine;
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- History of seizures;
- History of leukopenia or agranulocytosis;
- Uncorrected hypo- or hyperthyroidism;
- Clinically significant abnormal laboratory tests;
- Concomitant use carbamazepine or other concomitant medication with primarily CNS activity; Has received an investigational drug within 30 days of enrollment.
- Has received an antidepressant within 4 weeks prior to Visit 1 (8 weeks for fluoxetine);
- No course of ECT (electroconvulsive therapy) within the preceding 4 weeks to Visit 1;
- Treatment with an injectable depot neuroleptic within less than one dosing interval prior to Visit 1;
- Has an acute or chronic illness likely to impair drug absorption, distribution, metabolism or excretion;
- General MRI exclusion criteria.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institute of Mental Health (NIMH)
Bethesda, Maryland, 20892
About this study
Official title: A Double Blind Study Examining the Efficacy of Clozapine and a Study of the Pathophysiology in Treatment Resistant Mania
The purpose of this study is to evaluate the safety and effectiveness of clozapine as a treatment for the manic phase of bipolar disorder.
A significant proportion of manic patients either do not respond adequately to conventional treatment or cannot tolerate the adverse effects associated with therapeutic doses of these agents. Clozapine may be a safe and effective treatment for mania. However, the efficacy of clozapine as an alternative therapy in treatment-resistant bipolar disorder mania has not been extensively researched.
The study will be conducted in three phases. Phase 1 is a screening phase that will take place for 2 to 7 days. Participants will undergo a baseline positron emission tomography (PET) scan of the brain at the end of this period. In Phase 2, participants will be randomly assigned to receive either clozapine or placebo (an inactive pill) for 3 weeks. They may also receive lorazepam for the first 10 days of Phase 2. After 3 weeks, patients treated with clozapine will undergo a second PET scan. During Phase 3, participants who received placebo and did not improve will be offered clozapine for 3 weeks. Those who received clozapine and did not improve will receive other treatment for 3 weeks. At the end of Phase 3, participants who were treated with clozapine will have another PET scan.
Read the detailed description
A significant proportion of manic patients either do not respond adequately to conventional treatment (lithium, valproate or carbamazepine (with or without antipsychotic drugs), or cannot tolerate the adverse effects associated with therapeutic doses of these agents. Thus, a need exists for additional effective treatments. Preliminary studies by our group suggest that clozapine may have antimanic actions and be effective in treatment-resistant bipolar disorder. However, the efficacy of clozapine as an alternative therapy in treatment-resistant mania has never been subjected to definitive study with an adequate number of subjects. Thus, we propose to conduct the largest and only double-blind, placebo-controlled trial to date, of clozapine, in bipolar manic patients who were unresponsive or intolerant to six weeks of treatment with lithium, valproate, carbamazepine and at least one antipsychotic drug. The specific aims of this investigation are to 1) assess the acute treatment efficacy of clozapine in treatment-resistant mania, 2) to investigate the functional anatomical correlates of mania, and 3) to investigate the effects of clozapine treatment on cerebral glucose metabolism and metabolic correlates of effective antimanic, clozapine treatment. Forty-two subjects (two groups of 21 each) will be randomly assigned to treatment with clozapine or placebo for three weeks. We anticipate that a maximum of 33% of patients will be withdrawn from the acute phase of the study due to reasons such as intolerable adverse effects or withdrawal of consent. Thus, we expect the entered sample to yield 14 completed subjects per cell. This sample size will allow for adequate statistical power to test the hypotheses stated above. Patients, ages 18-65, with a diagnosis of bipolar I disorder manic or mixed (with or without psychotic features), will be randomized to double-blind treatment to receive either clozapine (200-550 mg/day) or placebo, for a period of 3 weeks. Following this acute period, the patients will receive either open-label clozapine or treatment as clinically indicated. If clozapine is found effective in treatment-resistant mania, it would be a significant step forward in the treatment of these patients and would have major health implications. In addition, it would establish a gold standard against which newer treatments can be compared to. Finally, glucose metabolism images will be obtained using PET and [F-18] FDG at baseline and following 3 weeks of clozapine treatment to investigate the functional anatomical correlates of mania and to compare drug-induced metabolic changes between responders and nonresponders.
- Conditions
- Bipolar Disorder
- Being tested
- Clozapine
- Keywords
- Placebo Controlled, Atypical Anti-Psychotic, Bipolar Mood Disorder, Positron Emission Tomography, Dopamine Receptor Blockade, Antimanic, Mania, Pathophysiology, Treatment-Resistant, Mood Disorder, BPD, Bipolar
- Medical subject headings
- Bipolar Disorder, Mania, Mood Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ClozapineDrug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Jan 2002 (estimated)
- Study startJan 2002
- Study completionOct 2005
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 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
- Primary purpose
- Treatment
- Enrolment
- 42 participants
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
- NCT00029458
- Sponsor's protocol ID
- 020085
- Other IDs
- 02-M-0085
- Status last verified
- Oct 2005
- First submitted
- 11 Jan 2002
- Last updated
- 4 Mar 2008
- Results posted
- No
Publications
Ahlfors UG, Baastrup PC, Dencker SJ, Elgen K, Lingjaerde O, Pedersen V, Schou M, Aaskoven O. Flupenthixol decanoate in recurrent manic-depressive illness. A comparison with lithium. Acta Psychiatr Scand. 1981 Sep;64(3):226-37. doi: 10.1111/j.1600-0447.1981.tb00778.x.
PubMed 7324992Altshuler LL, Bartzokis G, Grieder T, Curran J, Mintz J. Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophrenia: an MRI study demonstrating neuroanatomic specificity. Arch Gen Psychiatry. 1998 Jul;55(7):663-4. doi: 10.1001/archpsyc.55.7.663. No abstract available.
PubMed 9672058American Psychiatric Association Practice Guidelines. Practice guideline for the treatment of patients with borderline personality disorder. American Psychiatric Association. Am J Psychiatry. 2001 Oct;158(10 Suppl):1-52. No abstract available.
PubMed 11665545
Study at a glance
From the registry record, last updated by the sponsor on 4 Mar 2008. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Double Blind Study Examining the Efficacy of Clozapine and a Study of the Pathophysiology in Treatment Resistant Mania
- ClinicalTrials.gov ID
- NCT00029458
- Acronym / sponsor ID
- 020085
- Conditions
- Bipolar Disorder
- Keywords
- Placebo Controlled, Atypical Anti-Psychotic, Bipolar Mood Disorder, Positron Emission Tomography, Dopamine Receptor Blockade, Antimanic, Mania, Pathophysiology
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 42 participants
- Lead sponsor
- National Institute of Mental Health (NIMH)US National Institutes of Health
- Study start
- Jan 2002
- Study completion
- Oct 2005
- First posted
- 14 Jan 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 evaluate the safety and effectiveness of clozapine as a treatment for the manic phase of bipolar disorder.
A significant proportion of manic patients either do not respond adequately to conventional treatment or cannot tolerate the adverse effects associated with therapeutic doses of these agents. Clozapine may be a safe and effective treatment for mania. However, the efficacy of clozapine as an alternative therapy in treatment-resistant bipolar disorder mania has not been extensively researched.
The study will be conducted in three phases. Phase 1 is a screening phase that will take place for 2 to 7 days. Participants will undergo a baseline positron emission tomography (PET) scan of the brain at the end of this period. In Phase 2, participants will be randomly assigned to receive either clozapine or placebo (an inactive pill) for 3 weeks. They may also receive lorazepam for the first 10 days of Phase 2. After 3 weeks, patients treated with clozapine will undergo a second PET scan. During Phase 3, participants who received placebo and did not improve will be offered clozapine for 3 weeks. Those who received clozapine and did not improve will receive other treatment for 3 weeks. At the end of Phase 3, participants who were treated with clozapine will have another PET scan.
Detailed description
A significant proportion of manic patients either do not respond adequately to conventional treatment (lithium, valproate or carbamazepine (with or without antipsychotic drugs), or cannot tolerate the adverse effects associated with therapeutic doses of these agents. Thus, a need exists for additional effective treatments. Preliminary studies by our group suggest that clozapine may have antimanic actions and be effective in treatment-resistant bipolar disorder. However, the efficacy of clozapine as an alternative therapy in treatment-resistant mania has never been subjected to definitive study with an adequate number of subjects. Thus, we propose to conduct the largest and only double-blind, placebo-controlled trial to date, of clozapine, in bipolar manic patients who were unresponsive or intolerant to six weeks of treatment with lithium, valproate, carbamazepine and at least one antipsychotic drug. The specific aims of this investigation are to 1) assess the acute treatment efficacy of clozapine in treatment-resistant mania, 2) to investigate the functional anatomical correlates of mania, and 3) to investigate the effects of clozapine treatment on cerebral glucose metabolism and metabolic correlates of effective antimanic, clozapine treatment. Forty-two subjects (two groups of 21 each) will be randomly assigned to treatment with clozapine or placebo for three weeks. We anticipate that a maximum of 33% of patients will be withdrawn from the acute phase of the study due to reasons such as intolerable adverse effects or withdrawal of consent. Thus, we expect the entered sample to yield 14 completed subjects per cell. This sample size will allow for adequate statistical power to test the hypotheses stated above. Patients, ages 18-65, with a diagnosis of bipolar I disorder manic or mixed (with or without psychotic features), will be randomized to double-blind treatment to receive either clozapine (200-550 mg/day) or placebo, for a period of 3 weeks. Following this acute period, the patients will receive either open-label clozapine or treatment as clinically indicated. If clozapine is found effective in treatment-resistant mania, it would be a significant step forward in the treatment of these patients and would have major health implications. In addition, it would establish a gold standard against which newer treatments can be compared to. Finally, glucose metabolism images will be obtained using PET and [F-18] FDG at baseline and following 3 weeks of clozapine treatment to investigate the functional anatomical correlates of mania and to compare drug-induced metabolic changes between responders and nonresponders.
Study design
- Primary purpose
- Treatment
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (9 listed)
- Males or females 18 to 65 years of age;
- Diagnosis: DSM-IV Bipolar I Disorder, current episode manic or mixed with or without psychotic features as determined by SCID-P. This criteria includes the following diagnoses: 296.4X, Bipolar I Disorder, Most Recent Episode Manic, and 296.6X, Bipolar I Disorder, Most Recent Episode Mixed;
- YMRS greater than or equal to 20 at Visits 1 and 2;
- No decrease in total score of YMRS of greater than or equal to 20% during washout (between Visits 1 and 2);
- Meet criteria for treatment resistance.
Key exclusion criteria (16 listed)
- WBC count is less than 3500/mm(3) or history of a myeloproliferative disorder.
- History of meeting criteria for DSM-IV criteria for schizophrenia or other psychotic disorder;
- History of DSM-IV substance abuse or dependence, including alcohol within the last four weeks;
- Acute or unstable medical illnesses, (e.g., delirium, metastatic cancer, unstable diabetes, decompensated cardiac, hepatic, renal or pulmonary disease, or stroke or myocardial infarction within the last six months);
- Current pregnancy or plan to become pregnant during the first three months (the duration of the study) in woman of childbearing age; breast-feeding in woman with infants;
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 |
|---|---|---|
| Clozapine | Drug | – |
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 4 Mar 2008.
- Background: PubMed 7324992Ahlfors UG, Baastrup PC, Dencker SJ, Elgen K, Lingjaerde O, Pedersen V, Schou M, Aaskoven O. Flupenthixol decanoate in recurrent manic-depressive illness. A comparison with lithium. Acta Psychiatr Scand. 1981 Sep;64(3):226-37. doi: 10.1111/j.1600-0447.1981.tb00778.x.
- Background: PubMed 9672058Altshuler LL, Bartzokis G, Grieder T, Curran J, Mintz J. Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophrenia: an MRI study demonstrating neuroanatomic specificity. Arch Gen Psychiatry. 1998 Jul;55(7):663-4. doi: 10.1001/archpsyc.55.7.663. No abstract available.
- Background: PubMed 11665545American Psychiatric Association Practice Guidelines. Practice guideline for the treatment of patients with borderline personality disorder. American Psychiatric Association. Am J Psychiatry. 2001 Oct;158(10 Suppl):1-52. No abstract available.
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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 Clozapine in people with 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 9 inclusion and 16 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 4 Mar 2008. 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 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 NCT00029458, 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 4 Mar 2008.