Brain Derived Neurotrophic Factor as a Predictor of Response to Treatment in Bipolar Depression and Mania: 16-weeks Follow-up With Quetiapine XR

The recruitment status of this study is unknown because the information has not been verified recently.
Verified February 2011 by Hospital de Clinicas de Porto Alegre.
Recruitment status was  Recruiting
Sponsor:
Information provided by:
Hospital de Clinicas de Porto Alegre
ClinicalTrials.gov Identifier:
NCT00879307
First received: April 9, 2009
Last updated: February 15, 2011
Last verified: February 2011

April 9, 2009
February 15, 2011
March 2009
September 2011   (final data collection date for primary outcome measure)
Efficacy of quetiapine as a treatment for acute mania and depression, and of as a manutence treatment. [ Time Frame: 16 weeks ] [ Designated as safety issue: Yes ]
Same as current
Complete list of historical versions of study NCT00879307 on ClinicalTrials.gov Archive Site
Assess the pharmacodynamics of quetiapine by neurotrophins in blood samples. [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Brain Derived Neurotrophic Factor as a Predictor of Response to Treatment in Bipolar Depression and Mania: 16-weeks Follow-up With Quetiapine XR
Brain Derived Neurotrophic Factor as a Predictor of Response to Treatment in Bipolar Depression and Mania: 16-weeks Follow-up With Quetiapine XR

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.

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.

Interventional
Phase 3
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
BIPOLAR DISORDER
Drug: quetiapine
Use of quetiapine for 16 weeks in acute mania and depression
Other Name: SEROQUEL XR
Experimental: 1
Use of quetiapine
Intervention: Drug: quetiapine
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
100
September 2011
September 2011   (final data collection date for primary outcome measure)

Inclusion Criteria:

  1. Provision of written informed consent
  2. A diagnosis of Bipolar Disorder I by Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition revised (DSM-IV-TR)
  3. Males and females aged 18 to 65 years
  4. 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
  5. Able to understand and comply with the requirements of the study
  6. 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:

  1. Pregnancy or lactation
  2. Any DSM-IV Axis I disorder not defined in the inclusion criteria
  3. Patients who, in the opinion of the investigator, pose an imminent risk of suicide or a danger to self or others
  4. Known intolerance or lack of response to quetiapine fumarate, as judged by the investigator
  5. 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
  6. 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
  7. 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.
  8. Substance or alcohol dependence at enrolment (except dependence in full remission, and except for caffeine or nicotine dependence), as defined by DSM-IV criteria
  9. Opiates, amphetamine, barbiturate, cocaine, cannabis, or hallucinogen abuse by DSM-IV criteria within 4 weeks prior to enrolment
  10. Medical conditions that would affect absorption, distribution, metabolism, or excretion of study treatment
  11. Unstable or inadequately treated medical illness (e.g. congestive heart failure, angina pectoris, hypertension) as judged by the investigator
  12. Involvement in the planning and conduct of the study
  13. Previous enrolment in the present study.
  14. Participation in another drug trial within 4 weeks prior enrolment into this study or longer in accordance with local requirements
  15. 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
Both
18 Years to 65 Years
No
Contact: FLAVIO P KAPCZINSKI, MD, PHD 55-51-33598845 flavio.kapczinski@gmail.com
Contact: MARCIA SANTANNA, MD, PHD 55-51-33598846 mksantanna@gmail.com
Brazil
 
NCT00879307
07455
No
FLAVIO KAPCZINSKI, HOSPITAL DE CLINICAS DE PORTO ALEGRE-UNIVERSIDADE FEDERAL DO RIO GRANDE DO SUL
Hospital de Clinicas de Porto Alegre
Not Provided
Principal Investigator: FLAVIO KAPCZINSKI, MD, PHD Hospital de Clinicas de Porto Alegre
Hospital de Clinicas de Porto Alegre
February 2011

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP