Genetic Predictors of Lithium Response in Bipolar Disorder

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Department of Veterans Affairs
Sponsor:
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT00252577
First received: November 9, 2005
Last updated: August 6, 2014
Last verified: August 2014
  Purpose

The purpose of this study is to identify genetic predictors of lithium response in bipolar disorder.


Condition Intervention
Bipolar Disorder
Drug: Lithium treatment

Study Type: Observational
Study Design: Time Perspective: Prospective
Official Title: Genetic Studies of Psychiatric Illness

Resource links provided by NLM:


Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • Time to relapse [ Time Frame: every 2 months for 2 years ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples With DNA

DNA from patients with bipolar disorder


Estimated Enrollment: 130
Study Start Date: October 2005
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Group 1
Veterans with bipolar disorder
Drug: Lithium treatment
Lithium is a standard treatment for bipolar disorder. Patients will be stabilized on lithium monotherapy over a 3 month period, observed for one month, and then followed every 2 months in maintenance phase for 2 years

Detailed Description:

The long term focus of this research program has been identification of genes for bipolar disorder. We have recently obtained evidence from several lines of investigation to support the role of the gene for G protein receptor Kinase 3(GRK3) in bipolar disorder. Work to replicate and extend these results is continuing under NIH funding. In this clinical we will extend our work into Pharmacogenetics to attempt to identify genes that are associated with medication response in bipolar disorder. Lithium is the first mood stabilizer medication and remains a mainstay of treatment. Many patients have an excellent response to lithium, tolerate it well, and are stabilized for years, while others do not. The reasons for this difference in response are unclear, but it is likely that genetic factors make a substantial contribution. The lack of good predictors of response frequently result in a time consuming trial and error clinical process to find the best medication. Such a trial and error process can take months with prolongation of patient suffering. Hence, there is a strong clinical need for predictors. We have conducted a preliminary study with 92 lithium responders and 92 non-responders identified through retrospective detailed history and chart review. These subjects have been genotyped at 88 SNP markers in 9 candidates genes relevant to lithium presumed mechanism of action for bipolar disorder. Four SNP markers in three genes showed nominally significant association to lithium response. One of the SNPs in the gene for NTRK2, the receptor for BDNF, Showed a strong association in patients who had predominantly euphoric a opposed to dysphoric mania (p=0.0005). Many data argue for the role of BDNF in the mechanism of antidepressants and mood stabilized action as well as susceptibility to bipolar disorder. No association was observed in those with dysphoric mania. This suggests that variations in this gene may operate in a clinically and genetically distinct subset of patients. It also argues for the importance of incorporating clinical subtypes into such analyses. These pilot results are preliminary but suggest the feasibility of such an approach. We will conduct a prospective trial of lithium monotherapy in 100 patients with bipolar disorder. 200 patients who are unstable, mildly to moderately ill and not on lithium will be screened and then entered into 16-week stabilization phase where they will be treated and switched to lithium monotherapy. Patient stable on lithium will also be entered and other mediations withdrawn. After stabilization patients will be followed for one year or until a mood episode requires intervention. It is expected that 50% of patients will be stabilized and therefore 100 patients will enter the maintenance phase. Time to relapse and pharmacological intervention will be the primary outcome measure. This prospective sample will be used to replicate previous results at the NTRK2 and other genes. Analyses will be conducted to test for differences in survival curves between different genotypic group. Genomic control methods will be employed to detect or correct for possible stratification and heterogeneity. Clinical features of illness such as dysphoric mania, family history and rapid cycling will be employed as co-variates. Multivariate methods will also be employed in order to attempt to develop a multi-gene predictor of lithium response.

  Eligibility

Ages Eligible for Study:   21 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Veterans with bipolar disorder

Criteria

Inclusion Criteria:

  • Are 18 years of age or older;
  • Have a diagnosis of Bipolar Affective Disorder, I or II;
  • Have no contraindications, allergies, or previous adverse events or treatment failures with lithium;
  • Women who are not currently pregnant and are willing and able to use birth control;
  • Are clinically appropriate to treat with lithium.

Exclusion Criteria:

  • DSM-IV Axis I Diagnosis: other primary comorbid axis I disorders such as: schizophrenia, schizoaffective disorder, delusional disorder;
  • Alcohol or Substance Dependence: meets criteria for dependence within past 3 months;
  • Unstable Medial Conditions: Life threatening or unstable medical condition that require active adjustment of medications by medical history; or
  • Medical Conditions: concomitant medical condition that would preclude the use of lithium (i.e.: renal failure, head trauma with loss of consciousness, or clinically significant cardiac, renal, hepatic, neoplastic, or cardiovascular disease);
  • Concomitant treatment with the following medications (during maintenance Phase): antipsychotics, antidepressants, antianxiety agent with the exception of benzodiazepines, to be used if needed for anxiety or insomnia, not to exceed 10 doses/week, or mood stabilizers with the exception of lithium; and
  • Active suicidal or homicidal ideations as elicited in the interviews.
  • Stable and doing well on a mood stabilizer other than lithium.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00252577

Contacts
Contact: Anna Demodena (858) 642-3974 Anna.Demodena@va.gov
Contact: Susan G Leckband (858) 552-8585 ext 5337 susan.leckband@va.gov

Locations
United States, California
VA San Diego Healthcare System, San Diego Recruiting
San Diego, California, United States, 92161
Contact: Anna Demodena    858-642-3974    Anna.Demodena@va.gov   
Contact: Susan G Leckband    (858) 552-8585 ext 5337    susan.leckband@va.gov   
Principal Investigator: John Kelsoe, MD         
Sponsors and Collaborators
Investigators
Principal Investigator: John Kelsoe, MD VA San Diego Healthcare System, San Diego
  More Information

Additional Information:
No publications provided

Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT00252577     History of Changes
Other Study ID Numbers: MHBA-023-05S
Study First Received: November 9, 2005
Last Updated: August 6, 2014
Health Authority: United States: Federal Government

Keywords provided by Department of Veterans Affairs:
Lithium
Pharmacogenetics

Additional relevant MeSH terms:
Bipolar Disorder
Affective Disorders, Psychotic
Mood Disorders
Mental Disorders
Lithium
Lithium Carbonate
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Psychotropic Drugs
Antimanic Agents
Antidepressive Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 18, 2014