Genetic Predictors of Lithium Response in Bipolar Disorder

The long term focus of this research program has been identification of genes for bipolar
disorder. The investigators 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 the investigators will extend the investigators' 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.
The investigators 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 single nucleotide polymorphism (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 neurotrophic receptor tyrosine kinase 2 (NTRK2), the receptor
for brain-derived neurotrophic factor (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. The investigators 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.

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.