Clozapine for Treatment-Resistant Mania
Information source: National Institutes of Health Clinical Center (CC)
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Bipolar Disorder
Intervention: Clozapine (Drug)
Phase: Phase 2
Status: Completed
Sponsored by: National Institute of Mental Health (NIMH)
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 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.
Clinical Details
Official title: A Double Blind Study Examining the Efficacy of Clozapine and a Study of the Pathophysiology in Treatment Resistant Mania
Study design: Treatment, Safety/Efficacy Study
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.
Eligibility
Minimum age: N/A.
Maximum age: N/A.
Gender(s): Both.
Criteria:
INCLUSION CRITERIA:
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;
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.
EXCLUSION CRITERIA:
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;
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.
Locations and Contacts
National Institute of Mental Health (NIMH), Bethesda, Maryland 20892, United States
Additional Information
Related 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. Altshuler 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. No abstract available. American 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.
Starting date: January 2002
Ending date: October 2005
Last updated: March 3, 2008
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