BIPOLAR DISORDERPhase 3NCT00879307
Brain Derived Neurotrophic Factor as a Predictor of Response to Treatment in Bipolar Depression and Mania: 16-weeks Follow-up With Quetiapine XR
A Phase 3 study testing quetiapine in people with BIPOLAR DISORDER, run by Hospital de Clinicas de Porto Alegre at 1 site in Brazil.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- BIPOLAR DISORDER
- What is being tested?
- quetiapine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 100 participants
- Where
- 1 siteBrazil
- Study dates
- Mar 2009to Sep 2011
- Phase
- Phase 3
- 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
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
Who cannot join
- 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
- Known intolerance or lack of response to quetiapine fumarate, as judged by the investigator
- 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
Show all 22Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
Brazil1 site, 1 recruiting
- Recruiting
Hospital de Clinicas de Porto Alegre
Porto Alegre, Rio Grande do Sul, 90035003
FLAVIO KAPCZINSKI, MD, PHD
About this study
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.
Read the 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.
- Conditions
- BIPOLAR DISORDER
- Being tested
- quetiapine
- Medical subject headings
- Bipolar Disorder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
quetiapineDrug
Also called SEROQUEL XR
Use of quetiapine for 16 weeks in acute mania and depression
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | Use of quetiapine Receives: Drug: quetiapine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Efficacy of quetiapine as a treatment for acute mania and depression, and of as a manutence treatment.
Measured: 16 weeks
Secondary outcomes (1)
Assess the pharmacodynamics of quetiapine by neurotrophins in blood samples.
Measured: 16 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Apr 2009 (estimated)
- Study startMar 2009
- Primary completionSep 2011 (estimated)
- Study completionSep 2011 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)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 Hospital de Clinicas de Porto AlegreThe 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 3
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Hospital de Clinicas de Porto Alegre
- Sponsor type
- University, hospital or other
- Investigators
- FLAVIO KAPCZINSKI, MD, PHD, Principal investigator, Hospital de Clinicas de Porto Alegre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00879307
- Sponsor's protocol ID
- 07455
- Status last verified
- Feb 2011
- First submitted
- 9 Apr 2009
- Last updated
- 16 Feb 2011
- Results posted
- No
- Data monitoring committee
- No
Publications
Grande I, Kapczinski F, Stertz L, Colpo GD, Kunz M, Cereser KM, Kauer-Sant'Anna M, Frey B, Vieta E, Magalhaes PV. Peripheral brain-derived neurotrophic factor changes along treatment with extended release quetiapine during acute mood episodes: an open-label trial in drug-free patients with bipolar disorder. J Psychiatr Res. 2012 Nov;46(11):1511-4. doi: 10.1016/j.jpsychires.2012.08.017. Epub 2012 Aug 30.
PubMed 22939945
Study at a glance
From the registry record, last updated by the sponsor on 16 Feb 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Brain Derived Neurotrophic Factor as a Predictor of Response to Treatment in Bipolar Depression and Mania: 16-weeks Follow-up With Quetiapine XR
- ClinicalTrials.gov ID
- NCT00879307
- Acronym / sponsor ID
- 07455
- Conditions
- BIPOLAR DISORDER
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- Hospital de Clinicas de Porto AlegreUniversity, hospital or other
- Study start
- Mar 2009
- Primary completion
- Sep 2011 (estimated)
- Study completion
- Sep 2011 (estimated)
- First posted
- 10 Apr 2009 (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.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Drug: quetiapineUse of quetiapine |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (22 listed)
- 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
- Known intolerance or lack of response to quetiapine fumarate, as judged by the investigator
- 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
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 |
|---|---|---|
| quetiapineAlso: SEROQUEL XRUse of quetiapine for 16 weeks in acute mania and depression | Drug | 1 |
Primary outcome
Efficacy of quetiapine as a treatment for acute mania and depression, and of as a manutence treatment.
Time frame: 16 weeks
1 secondary outcome
Assess the pharmacodynamics of quetiapine by neurotrophins in blood samples.
Time frame: 16 weeks
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Feb 2011.
- Derived from this study: PubMed 22939945Grande I, Kapczinski F, Stertz L, Colpo GD, Kunz M, Cereser KM, Kauer-Sant'Anna M, Frey B, Vieta E, Magalhaes PV. Peripheral brain-derived neurotrophic factor changes along treatment with extended release quetiapine during acute mood episodes: an open-label trial in drug-free patients with bipolar disorder. J Psychiatr Res. 2012 Nov;46(11):1511-4. doi: 10.1016/j.jpsychires.2012.08.017. Epub 2012 Aug 30.
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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.
FLAVIO KAPCZINSKI, MD, PHD principal investigator
Hospital de Clinicas de Porto Alegre
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing quetiapine in people with BIPOLAR DISORDER, run by Hospital de Clinicas de Porto Alegre at 1 site in Brazil.
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 6 inclusion and 22 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: status not confirmed, as of the sponsor's last update on 16 Feb 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 Brazil. 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact FLAVIO P KAPCZINSKI, MD, PHD (55-51-33598845, flavio.kapczinski@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Efficacy of quetiapine as a treatment for acute mania and depression, and of as a manutence treatment. (time frame: 16 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 NCT00879307, which also lists 1 linked publication.
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 16 Feb 2011.