- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00879632
Brain Derived Neurotrophic Factor as a Predictor of Response to Treatment in Bipolar Depression and Mania
Brain Derived Neurotrophic Factor as a Predictor of Response to Treatment in Bipolar Depression and Mania: 16-weeks Follow-up Study
Study Overview
Status
Conditions
Detailed Description
There is sound evidence that quetiapine is effective in the treatment of manic and depressive episodes associated with Bipolar Disorder (BD) (Yatham et al 2006). However, even with the development of effective new treatment options, not all patients respond to treatments available. Biological markers have been investigated as predictors of response to treatment and of remission of symptoms. This would explain in part the individual's differences in the response to treatment, taking into account the genetic variability plus environmental factors influencing specific biological markers. A potential biological marker of response to treatment in BD would be the levels of neurotrophins, as they are, in fact, altered during acute mood episodes (Cunha et al 2006). Among neurotrophins, the Brain-Derived Neurotrophic Factor (BDNF) has been repeatedly and consistently reported to be associated with BD physiopathology (Post 2007). Furthermore, medications that are known to be effective in BD, like lithium and divalproex, increase BDNF levels. Diverse sources of evidence provide support to the alteration of BDNF in mood disorders:
- Patients with major depressive disorder showed lower levels of BDNF and the treatment with antidepressants recovered those levels back to normal. (Gonul et al 2005).
- Studies with brain tissue (post-mortem) showed that BDNF levels were decreased only on those who were not on antidepressants. (Karege et al 2002).
- The polymorphism of BDNF gene was associated with response to treatment with lithium during maintenance phase. (Rybakowski et al. 2005).
- Our group showed that BDNF levels are decreased during mania and depression, but not during remission (Cunha et al 2006, Machado-Vieira et al. 2007). Therefore, BDNF appear to be involved in the mechanisms of acute mood episodes.
- Treatment with mood stabilizers, such as lithium and divalproex, increase BDNF levels (Frey et al. 2006).
Prediction of drug treatment response based on variation in genetic make up is a rapidly growing area. However, few studies examined the association between single nucleotide polymorphisms and drug response in bipolar disorder. The design of this study offers a unique opportunity to examine genetic predictors of drug response. Interestingly, a single nucleotide polymorphism at nucleotide196 (G/A) in the human BDNF gene at codon 66 (Val66Met) have been reported to be associated with a predisposition to BD in family-based studies (Rybakowski et al 2006, Green et al 2006). In humans, this polymorphism produces a valine - to - methionine substitution in the proBDNF protein and reduces the trafficking and secretion of BDNF protein. This is relevant because it has been estimated that 20-30% of the human population is heterozygous for the Met polymorphism of BDNF. Furthermore, there are consistent findings in BD regarding the association of Val66Met polymorphism of BDNF gene with prefrontal cognitive impairment, which was recently confirmed in a large sample of bipolar subjects (Rybakowski et al 2006). In addition, crosssectional studies showed that the polymorphism of BDNF gene (Val66Met) was associated with response to lithium prophylaxis, but findings were not universal (Rybakowski et al 2005, Masui et al 2006). However, there is a need for prospective studies in order to confirm these findings. It is possible that a single polymorphism of BDNF gene would have a negative impact of BDNF levels and, consequently, a negative impact in the response to treatment.
Despite consistent evidence of changes in BDNF levels during mood episodes and treatment, one important aspect remains unknown: Whether the change in BDNF levels is required for treatment response and whether the magnitude of change happens in portion with the response to treatment and remission of symptoms.
The hypothesis for this project is that those patients who have a good response to treatment are the same ones who show the greater increase in BDNF levels earlier in the course of treatment, and who are less likely to present a polymorphism of BDNF gene. Given this context, we aim to investigate BDNF levels prospectively in patients with BD, before, during and after the treatment with quetiapine and compare measures with response to treatment, as indicated by remission in symptoms. We also aim to investigate the polymorphism of BDNF gene (Val66Met) and its correlation with BDNF serum levels and treatment response.
Study Type
Enrollment (Anticipated)
Contacts and Locations
Study Locations
-
-
RS
-
Porto Alegre, RS, Brazil, 90035003
- Recruiting
- Hospital de Clínicas de Porto Alegre
-
Principal Investigator:
- FLAVIO KAPCZINSKI, MD, PHD
-
Contact:
- MARCIA SANTANNA, MD PHD
- Phone Number: 55-51-33598846
- Email: mksantanna@gmail.com
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
Description
Inclusion Criteria:
- Provision of written informed consent
- A diagnosis of Bipolar Disorder I by Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition revised (DSM-IV-TR)
- Males and females aged 18 to 65 years
- Female patients of childbearing potential must be using a reliable method of contraception and have a negative urine human chorionic gonadotrophin (HCG) test at enrolment
- Able to understand and comply with the requirements of the study
- Currently experiencing a manic, depressive or mixed mood episode, according to DSM-IV-TR. Patients must have a clear DSM-IV diagnosis, confirmed by SCID interview (Structured Clinical Interview for DSM disorders).
Exclusion Criteria:
- Pregnancy or lactation
- Any DSM-IV Axis I disorder not defined in the inclusion criteria
- Patients who, in the opinion of the investigator, pose an imminent risk of suicide or a danger to self or others
- Use of any of the following cytochrome P450 3A4 inhibitors in the 14 days preceding enrolment including but not limited to: ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin, troleandomycin, indinavir, nelfinavir, ritonavir, fluvoxamine and saquinavir
- Use of any of the following cytochrome P450 3A4 inducers in the 14 days preceding enrolment including but not limited to: phenytoin, carbamazepine, barbiturates, rifampin, St. John's Wort, and glucocorticoids
- Currently on psychotropic medication or administration of a depot antipsychotic injection within one dosing interval (for the depot) before randomisation. Wash-out of minimum of 2 weeks will be required for intake. Fluoxetine use or depot antipsychotics will require 6 weeks of wash-out prior to intake.
- Substance or alcohol dependence at enrolment (except dependence in full remission, and except for caffeine or nicotine dependence), as defined by DSM-IV criteria
- Opiates, amphetamine, barbiturate, cocaine, cannabis, or hallucinogen abuse by DSM-IV criteria within 4 weeks prior to enrolment
- Medical conditions that would affect absorption, distribution, metabolism, or excretion of study treatment
- Unstable or inadequately treated medical illness (e.g. congestive heart failure, angina pectoris, hypertension) as judged by the investigator
- Involvement in the planning and conduct of the study
- Previous enrolment in the present study.
- Participation in another drug trial within 4 weeks prior enrolment into this study or longer in accordance with local requirements
A patient with Diabetes Mellitus (DM) fulfilling one of the following criteria:
- Unstable DM defined as enrolment glycosylated hemoglobin (HbA1c) >8.5%.
- Admitted to hospital for treatment of DM or DM related illness in past 12 weeks.
- Not under physician care for DM
- Physician responsible for patient's DM care has not indicated that patient's DM is controlled.
- Physician responsible for patient's DM care has not approved patient's participation in the study
- Has not been on the same dose of oral hypoglycaemic drug(s) and/or diet for the 4 weeks prior to screening. For thiazolidinediones (glitazones) this period should not be less than 8 Weeks.
- Taking insulin whose daily dose on one occasion in the past 4 weeks has been more than 10% above or below their mean dose in the preceding 4 weeks Note: If a diabetic patient meets one of these criteria, the patient is to be excluded even if the treating physician believes that the patient is stable and can participate in the study.
Study Plan
How is the study designed?
Design Details
Cohorts and Interventions
Group / Cohort |
---|
1
TREATMENT AS USUAL
|
2
CONTROLS
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Hamilton depression raing scale and young mania rating scale
Time Frame: 16 weeks
|
16 weeks
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Serum BDNF levels as predictor of response to treatment
Time Frame: 16 weeks
|
16 weeks
|
Collaborators and Investigators
Investigators
- Principal Investigator: FLAVIO KAPCZINSKI, MD, PHD, Hospital de Clínicas de Porto Alegre
Study record dates
Study Major Dates
Study Start
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 07456
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on BIPOLAR DISORDER
-
ProgenaBiomeRecruitingBipolar Disorder | Bipolar I Disorder | Bipolar II Disorder | Bipolar Type I Disorder | Bipolar Disorder Mild | Bipolar Disorder Moderate | Bipolar Disorder SevereUnited States
-
Rush University Medical CenterThe Ryan Licht Sang Bipolar FoundationCompletedBipolar Disorder | Bipolar Depression | Bipolar I Disorder | Bipolar Disorder I | Bipolar Affective DisorderUnited States
-
University of PittsburghNational Alliance for Research on Schizophrenia and DepressionCompletedBipolar I Disorder | Bipolar II Disorder | Bipolar Disorder NOSUnited States
-
Region StockholmKarolinska InstitutetRecruitingBipolar Disorder | Bipolar Depression | Bipolar I Disorder | Bipolar II Disorder | Bipolar Affective Disorder; Remission in | Bipolar Affective Disorder, Currently Depressed, ModerateSweden
-
Hospital de Clinicas de Porto AlegreFederal University of Rio Grande do Sul; Hospital Moinhos de VentoActive, not recruitingBipolar Disorder | Bipolar Depression | Major Depressive Disorder | Bipolar I Disorder | Affective Disorder | Bipolar II DisorderBrazil
-
Medical University of South CarolinaMilken InstituteCompletedBipolar Disorder | Bipolar I Disorder | Bipolar II DisorderUnited States
-
Joshua RosenblatRecruitingBipolar Disorder | Bipolar Depression | Bipolar I Disorder | Bipolar II DisorderCanada
-
Mayo ClinicCompletedMajor Depressive Disorder, Bipolar I and Bipolar IIUnited States
-
Joshua RosenblatRecruitingBipolar Disorder | Bipolar Depression | Bipolar I Disorder | Bipolar II DisorderCanada
-
Myriad Genetic Laboratories, Inc.University of MinnesotaCompletedMajor Depressive Disorder, Bipolar I and Bipolar IIUnited States