The pharmacogenetics of lithium response depends upon clinical co-morbidity.
BACKGROUND
Based on results from randomized, controlled clinical trials, lithium monotherapy or lithium with the addition of an antipsychotic remains a first-line treatment option for both acute and long-term mood stabilization in bipolar mania. However, response to lithium is poor in bipolar patients who exhibit clinical characteristics such as rapid cycling and mixed manic states, suggesting that they may have a biologically and genetically distinct form of bipolar disorder. A test that could predict response to lithium based upon genetic factors would have significant clinical value.


METHODS
Eight clinical characteristics were assessed in 92 lithium responders and 92 nonresponders; all probands were from families recruited for linkage studies. Lithium response was rated retrospectively from a standardized interviews and medical records. Eight candidate genes were selected from those reported to be associated with susceptibility to illness, lithium response, or lithium mechanism of action. Sixty-seven single nucleotide polymorphisms (SNPs) were genotyped in these subjects and analyzed for association with the defined clinical characteristics.


RESULTS
Using q-value analysis for multiplicity correction, we found significant interactions between lithium response and SNPs (rs1387923 and rs1565445) in the gene encoding neurotrophic tyrosine kinase receptor type 2 (NTRK2) and suicidal ideation, and between SNP rs2064721 in the gene encoding inositol polyphosphate-1-phosphatase (INPP1) and post-traumatic stress disorder.


CONCLUSIONS
These data support the idea that response to lithium has a multi-genetic etiology dependent upon manifestations of other clinical co-diagnoses.
Bremer
Troy
T
Prediction Sciences, Inc., San Diego, California, USA. tbremer@predict.net
Diamond
Cornelius
C
McKinney
Rebecca
R
Shehktman
Tatyana
T
Barrett
Thomas B
TB
Herold
Chris
C
Kelsoe
John R
JR
D001714:Bipolar Disorder / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D054770:G-Protein-Coupled Receptor Kinase 3; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D018020:Lithium Compounds / Q000627:therapeutic use*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D020813:Receptor, trkB / Q000235:genetics; D012189:Retrospective Studies; D013313:Stress Disorders, Post-Traumatic / Q000150:complications*; D013405:Suicide / Q000523:psychology*; D051552:beta-Adrenergic Receptor Kinases / Q000235:genetics
D005819:Genetic Markers; D018020:Lithium Compounds; D020813:Receptor, trkB; D054770:G-Protein-Coupled Receptor Kinase 3; C517848:GRK3 protein, human; D051552:beta-Adrenergic Receptor Kinases; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; C053087:inositol-1,4-bisphosphate 1-phosphatase